A–Z of Haematology HAE-(Pre) 01/13/2005 05:09PM Page Ii HAE-(Pre) 01/13/2005 05:09PM Page Iii

HAE-(pre) 01/13/2005 05:09PM Page i

A–Z of Haematology HAE-(pre) 01/13/2005 05:09PM Page ii HAE-(pre) 01/13/2005 05:09PM Page iii

A–Z of Haematology

Barbara J. Bain MB BS FRACP FRCPath Reader in Diagnostic Haematology Honorary Consultant Haematologist Department of Haematology St Mary’s Hospital Campus Imperial College Faculty of Medicine London Rajeev Gupta MB ChB PhD MRCP MRCPath Clinical Research Fellow Section of Gene Function and Regulation The Institute of Cancer Research London HAE-(pre) 01/13/2005 05:09PM Page iv

© 2003 by Blackwell Publishing Ltd Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5018, USA Blackwell Publishing Ltd, Osney Mead, Oxford OX2 0EL, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton South, Victoria 3053, Australia Blackwell Verlag GmbH, Kurfürstendamm 57, 10707 Berlin, Germany

The right of the Authors to be identiﬁed as the Authors of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

First published 2003 by Blackwell Publishing Ltd

Library of Congress Cataloging-in-Publication Data

Bain, Barbara J. A-Z of haematology/Barbara Bain. p. ; cm. ISBN 1-40510-322-1 1. Hematology—Dictionaries. [DNLM: 1. Hematology—Dictionary—English. WH 13 B162a 2003] I. Title. RB145 .B245 2003 616.15’003—dc21 2002007250

ISBN 1-4051-0322-1

A catalogue record for this title is available from the British Library

Set in 8.5/10.5 Times by Graphicraft Limited, Hong Kong Printed and bound in the United Kingdom by MPG Books Ltd, Bodmin, Cornwall

Commissioning Editor: Maria Khan Editorial Assistant: Elizabeth Callaghan Production Editor: Charlie Hamlyn Production Controller: Kate Charman

For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com HAE-(pre) 01/13/2005 05:09PM Page v

Contents

Preface, vii

Online Resources, ix

A–Z of Haematology, 1

v HAE-(pre) 01/13/2005 05:09PM Page vi HAE-(pre) 01/13/2005 05:09PM Page vii

Preface

In this A–Z of Haematology we have mended by the human genome project, sought to be as comprehensive as possible, in upper case italics with Greek letters but we have nevertheless given particular being replaced by their Roman equivalent. emphasis to recent advances in molecular Approved names are given but where a haematology. We have detailed the im- gene is better known to haematologists by portant genes that have been implicated another name, we have mainly used that in haematological neoplasms and in con- name in further discussion. We have indic- stitutional haematological disorders. Blood ated how gene names (and some protein transfusion, haemostasis and thrombosis names) are derived from a longer descript- and immunology have not been neglected. ive phrase by means of bold print plus We have provided the reader with a com- underlining of the relevant letters, e.g. plete list of the molecules that have been PLZF—Promyelocytic Leukaemia Zinc assigned a Cluster of Designation (CD) Finger. However, bold print without under- number, with descriptions of their functions lining is used for another purpose, to indi- and patterns of expression in health and dis- cate that there is a relevant entry in the ease. Because of the emphasis we have given book. In order to avoid tedium, words and to the scientific basis of haematology and phrases that are used very frequently, e.g. related disciplines we believe that this work ‘acute myeloid leukaemia’ are not generally will be useful not only to haematologists but cross referenced in this manner. also to research scientists and to biomedical We wish to thank those who have scientists working in diagnostic laborator- helped with the provision of illustra- ies. Those working in cancer cytogenetics tions: the publisher of the late Professor and immunophenotyping will also find it a M. Bessis, Professor D. Catovsky, Dr W. valuable repository of relevant knowledge. Gedroyc, Miss C. Hughes, Mr R. Morilla, The very existence of such a book is indic- Ms L. Phelan, Ms Julia Pickard and the ative of the fact that a book still remains a Cytogenetics Department at Hammersmith highly convenient reference source. How- Hospital, Professor A. Polliack, Professor ever, for those who wish to seek further Lorna Secker-Walker, The North Trent information electronically we have pro- Cytogenetics Service at Sheffield Childrens vided a list of some of the more useful of the Hospital, the Kennedy Galton Institute and many websites available. the United Kingdom Cancer Cytogenetics It will be helpful to the reader to know Group. some of the conventions we have followed. All human genes are designated as recom- Barbara J. Bain and Rajeev Gupta

vii HAE-(pre) 01/13/2005 05:09PM Page viii HAE-(pre) 01/13/2005 05:09PM Page ix

Online Resources

General haematology American Society of Hematology www.hematology.org British Society for Haematology www.blacksci.co.uk/uk/society/bsh (use this site to access PubMed, Centers of Disease Control and Institute of Biomedical Science) European Hematology Association www.ehaweb.org British Committee for Standards in Haematology guidelines www.bcshguidelines.com/ (use this site to access Cells of the Blood, Haematological Malignancy Diagnostic Service and Hematology Digital Image Bank) Haematologists in Training www.hit.gb.com/ (use this site to access MRC Leukaemia Trials and an on line medical dictionary through doctors’ guide to internet and Guide to Internet Resources on Haematological Malignancies) Other general haematology www.bloodline.net

Chromosomes, genes and proteins—molecular haematology Cytogenetics in haematology Genetics and cytogenetics in Haematology www.infobiogen.fr/services/chromcancer/ Online Mendelian Inheritance in Man www.ncbi.nlm.nih.gov/omim/ Cardiff Human Gene Mutation Data Base www.uwcm.ac.uk/uwcm/mg/hgmd0.html Sources of probes for molecular genetic studies: Vysis www.vysis.com/hematology and Q-Biogene (previously Oncor) www.cambio.co.uk/starﬁsh/ Human proteins website www.ncbi.nlm.nih.gov/prow Websites of antibody manufacturers http://serotec.oxi.net/asp/index.html www.bdbiosciences.com www.vectorlabs.com Realtime PCR www.cgr.otago.ac.nz/SLIDES/7700/SLD001.HTM Chemokine review http://www.path.sunysb.edu/courses/syllabus/chemkin.htm Cytokine minireviews http://www.rndsystems.com/asp/g_sitebuilder.asp?BodyId=2

Haemoglobinopathies and thalassaemias http://globin.cse.psu.edu

ix HAE-(pre) 01/13/2005 05:09PM Page x

x Online Resources

Thrombosis and haemostasis The International Society on Thrombosis and Haemostasis www.med.unc.edu/isth/welcome The World Federation of Hemophilia www.wfh.org

Blood transfusion American Association of Blood Banks www.aabb.org British Blood Transfusion Society www.bbts.org.uk (use this site to access British blood transfusion guidelines) National Blood Service www.blood.co.uk Serious Hazards of Transfusion http://www.shot.demon.co.uk

Malaria http://www.rph.wa.gov.au/labs/haem/malaria/

Haematological neoplasms General http://cancerweb.ncl.ac.uk/cancernet.html (use this site to access an online medical dictionary) http://www.cancerindex.org/clinks2.htm The British National Lymphoma Investigation www.bnli.ucl.ac.uk/ Lymphoma Forum www.lymphoma.org.uk/lymphoma.htm The Leukaemia Research Fund www.dspace.dial.pipex.com/lrf-/ The UK Myeloma Forum www.ukmf.org.uk American Association for Cancer Research www.aacr.org (use this site for access to the ﬁve journals published by the AACR)

Abstracts and journals Entrez PubMed www.ncbi.nlm.nih.gov/ Blood www.bloodjournal.org/ Haematologica www.haematologica.it/main.html Online ﬂow cytometry cases www.ﬂowcases.org British Medical Journal www.bmj.com

Teaching sites www.hematology.org (click on educational materials) www.haem.net http://pathy.med.nagoya-u.ac.jp/atlas/doc/atlas.html www-medlib.med.utah.edu/WebPath/webpath.html HAE-A 01/13/2005 05:09PM Page 1

α alpha, the ﬁrst letter of the Greek alpha- receptor, a surface membrane structure bet, often used to designate polypeptide in T lymphocytes which permits antigen chains recognition α α 1 antitrypsin a serpin which inactivates error a statistically signiﬁcant differ- neutrophil elastase; mutation of the gene ence when no real difference exists; e.g. if α encoding 1 antitrypsin can lead to pro- the results of two treatment strategies are duction of a protein that inhibits coagula- statistically different with a probability of tion pathway proteases and leads to a P = 0.05 there is a 1 in 20 chance that bleeding disorder there is no real difference α chain (i) the alpha globin chain α globin cluster the cluster of genes on which is essential for formation of hae- chromosome 16 that includes the genes ζ α α moglobins A, A2 and F (ii) the heavy encoding , 2 and 1 chains (Fig. 1) chain of immunoglobulin A; two alpha α globin gene the HBA genes, gene map chains combine with two light chains (in a locus 16p13.3, encoding the α globin single molecule either kappa or lambda) chain of haemoglobin; there are two α to form a complete immunoglobulin globin genes, designated α2 and α1, on molecule (iii) part of the αβ T-cell each chromosome 16

Figure 1 α and β globin gene clusters. The alpha and beta globin gene clusters on chromosomes 11 and 16 respectively. The β cluster has an upstream locus control region (LCR) and ε, Gγ, Aγ, δ and β genes; there is one pseudogene, ψβ. The α cluster has an upstream H40 regulatory region and ζ α α ψζ ψα , 2 and 1 globin chain genes; there are two pseudogenes, and .

Regulatory element— locus control region

LCR ε GγψβδβAγ 5' 3' Chromosome 11 Direction of transcription

Regulatory element

ψζ ψα α α HS-40 ζ 1 2 1 5' 3'

Chromosome 16 Direction of transcription

1 HAE-A 01/13/2005 05:09PM Page 2

2 α heavy chain disease

α heavy chain disease a plasma cell is a widely expressed component of a dyscrasia characterized by secretion of multi-protein complex that negatively the heavy chain of immunoglobulin A regulates cellular responses to various α naphthyl acetate esterase (ANAE) mitogenic signals an enzyme belonging to the non-specific ABL a gene, Abelson murine leukaemia esterase group of enzymes, strongly viral oncogene homologue 1, gene map expressed in cells of the monocytic and locus 9q34; cellular homologue of v-abl, a megakaryocytic lineages gene in the Abelson murine leukaemia α naphthyl butyrate esterase (ANBE) retrovirus which is involved in some an enzyme belonging to the non-specific murine leukaemias; encodes a non- esterase group of enzymes, strongly ex- receptor tyrosine kinase; ABL con- pressed in cells of the monocytic lineage tributes to: α satellite DNA repeat sequences at • the BCR-ABL fusion gene in the centromere of a chromosome; the t(9;22)(q34;q11) associated with chronic sequences differ between chromosomes, granulocytic leukaemia and with permitting the development of cen- Philadelphia-positive acute lymphoblas- tromeric probes that identify different tic and acute myeloid leukaemias chromosomes • the ETV6-ABL fusion gene in chronic α thalassaemia a group of thalas- myeloid leukaemias, acute myeloid leuk- saemias characterized by deletion or, less aemia and acute lymphoblastic leukaemia often, altered structure and reduced associated with t(9;12)(q34;p13) and var- function of one or more of the α globin iant translocations genes (see also α thalassaemia trait, Both BCR-ABL and ETV6-ABL are haemoglobin H disease and haemoglobin inhibited by the ABL tyrosine kinase Bart’s hydrops fetalis) (Fig. 2) inhibitor, imatinib mesylate (STI571) α thalassaemia trait a minor hae- ABL is amplified by segmental jump- matological abnormality resulting from ing translocations in some patients with deletion of one or two of the four α therapy-related acute myeloid leukaemia globin genes; includes heterozygosity and abnormal localization of immature homozygosity for α+ thalassaemia, when precursors (ALIP) location of myelo- one of two α genes on a chromosome blasts and promyelocytes in the centre is deleted, and heterozygosity for α0 of the intertrabecular space rather than thalassaemia, when both α genes on a adjacent to trabeculae or surrounding single chromosome are deleted (see Fig. 2) arterioles A an abbreviation for the purine, adenine ABO blood group system a blood ABC7 a gene, gene map locus Xq13, group system in which A and B alleles at encoding ATP Binding Cassette trans- the ABO locus at 9q34 encode specific porter 7, a mitochondrial protein, muta- glycosyltransferases that modify a pre- tion of which can cause sideroblastic cursor disaccharide (Fig. 3 and Table 1, anaemia with spino-cerebellar ataxia p. 4); this precursor is part of a glyco- aberrant diverging from normal, e.g. protein or glycolipid which, when unmod- expression of an antigen which is inap- ified, expresses the H antigen; the O allele propriate for a lineage does not encode a functional transferase abetalipoproteinaemia inherited ab- so that homozygosity for O means H is sence of beta lipoproteins, associated with expressed but not A or B; ABO antigens acanthocytosis are expressed on all blood cells and many ABI1 a gene, Abl-Interactor 1, gene other body cells (see also Bombay blood map locus 10p11.2, which contributes group); ABO chimaerism can result from to the MLL-ABI1 fusion gene in M4 constitutional mosaic trisomy 9 acute myeloid leukaemia associated with abortion spontaneous or induced term- t(10;11)(p11.2;q23); ABI1 encodes spec- ination of pregnancy before the fetus is trin SH3 domain-binding protein 1, which viable, e.g. before 28 weeks HAE-A 01/13/2005 05:09PM Page 3

abortion 3

Figure 2 α thalassaemias. The terminology applied to the alpha thalassaemias; most of the alpha thalassaemias result from deletion of one or both alpha genes at a locus and in some cases the zeta gene is also deleted; α+ thalassaemia indicates that there is one remaining alpha gene at the locus whereas α0 thalassaemia indicates that both genes at a locus are deleted; in the case of –α3.7 the remaining gene at the locus is an α2α1 fusion gene; non-deletional thalassaemia refers to the less common alpha thalassaemias resulting from mutation rather than deletion of an alpha gene, the gene being designated αT, e.g. αTsaudi .

Genotype Diagrammatic representation Designation Phenotype

αα/αα Normal Normal ζαα ζαα 2 1 2 1

α+ thalassaemia α3.7 αα – / heterozygosity ζαα ζαα 2 1 2 1

α+ thalassaemia α3.7 α3.7 – /– homozygosity ζαα ζαα 2 1 2 1

α thalassaemia Non-deletional trait αTα/αα (α+) thalassaemia ζααT ζαα 1 2 1 heterozygosity

α0 thalassaemia SEA αα –– / heterozygosity ζζαα 2 1

α0 thalassaemia THAI αα –– / heterozygosity ζαα 2 1

α0α+ thalassaemia ––THAI/–α4.2 compound ζα heterozygosity 1 Haemoglobin H disease Non-deletional αTα/αTα (α+) thalassaemic ζααT ζααT 1 1 homozygosity

α0 thalassaemia SEA SEA –– /–– homozygosity ζζ Haemoglobin Bart's hydrops α0 thalassaemia fetalis ––SEA/––THAI compound ζ heterozygosity HAE-A 01/13/2005 05:09PM Page 4

4 abortion

Figure 3 ABO antigens. The formation of ABO antigens: (a) formation of H antigen and formation of A and B antigens from H; (b) the loci, the alleles and the transferases involved in the formation of ABO antigens. * The A2 allele encodes a less efﬁcient transferase that does not utilize types 3 and 4 disaccharide; A3 and Ax also encode less efﬁcient transferases.

(a) (type 1 mainly in plasma, Type 1–4 disaccharides types 2, 3 and 4 on cells)

α-2-L-fucosyltransferase (encoded by H allele of FUT1 gene)

α-3-N-acetyl D α-3-D galactosyltransferase galactosylaminyltransferase (encoded by B allele at (encoded by the ABO locus) A1 allele* at the ABO locus) AB

(b) Locus Allele Transferase

H α-2-L-fucosyltransferase FUT1 h nil α-3-N-acetyl-D- A galactosaminyltransferase ABO α-3-D B galactosyltransferase

O nil

Table 1 Genotypes and resultant phenotypes of the ABO blood group system; the antibodies usually present in individuals of different ABO groups are also shown.

Alleles* at ABO locus Antigens expressed Antibodies

AO or AA A anti-B BO or BB B anti-A AB A + B nil OO nil anti-A + anti-B

* The A allele may be either A1 or A2; A2 and rare alleles of A encode a less efﬁcient transferase. HAE-A 01/13/2005 05:09PM Page 5

acquired 5

Figure 4 An acanthocyte and a discocyte. Scanning electron micrographs of an acanthocyte and a normal shaped red cell, a discocyte.

absorbance the degree of absorption of acid (i) a hydrogen-containing substance light that yields a free hydrogen ion and a acaeruloplasminaemia an inherited, cation on dissociation (ii) having a low autosomal recessive condition, resulting pH from mutation in the caeruloplasmin acidified serum test see acid lysis test gene on chromosome 3q, and consequent acid-fast bacillus (AFB) a micro- deficiency of caeruloplasmin ferroxidase; organism, usually a bacillus of the genus there is iron overload with low serum Mycobacteria, um, which, when stained iron, normal transferrin concentration with a Ziehl–Neelsen stain, retains its and moderately elevated serum ferritin colour when exposed to acid acanthocyte an erythrocyte covered acid lysis test a test for paroxysmal with a small number of spicules of vari- nocturnal haemoglobinuria and type II able length, thickness and shape (Fig. 4) congenital dyserythropoietic anaemia acanthocytosis the presence of (Fig. 5) acanthocytes acidophilic having an affinity for acid accelerated phase a term used to dyes such as eosin describe a more aggressive phase of acidosis having a blood pH less than 7.35 chronic granulocytic leukaemia acid phosphatase this is a generic term accuracy the closeness of a measured for an enzyme that works optimally at value to the true value acid pH to release phosphate groups acentric having no centromere; acentric from complex molecules, e.g. from the chromosomes cannot become attached to serine, threonine and tyrosine residues of the mitotic spindle and consequently may proteins; they are usually fairly target not be present in either daughter nucleus specific; many lymphoid and myeloid ACHE a gene, gene map locus 7q22, alle- cells have acid phosphatase activity that les of which encode the Yta and Ytb anti- is demonstrable cytochemically (see also gens of the Cartwright blood group alkaline phosphatase) system, these antigens being expressed aCML atypical chronic myeloid leukaemia on GPI-linked Acetylcholinesterase acquired not present at birth; the term achlorhydria absence of gastric acid generally implies a condition or charac- secretion, a feature of pernicious anaemia teristic that is not inherited HAE-A 01/13/2005 05:09PM Page 6

6 acquired angio-oedema

Figure 5 The acid lysis test. The principle of the acid lysis test (Ham test) is that some of the patient’s cells lyse when exposed to acidified fresh normal serum (containing complement), conveying a pink or red colour to the supernatant of the centrifuged test sample; lysis does not occur when the serum has not been acidified or when complement in the serum has been inactivated by prior heating. Normal red cells, which are not susceptible to complement-induced lysis in acidified serum, do not lyse in any of these circumstances.

Test Controls

Serum Normal Normal Inactive Normal Normal Inactive Acid No Yes Yes No Yes Yes Cells Patient Patient Patient Normal Normal Normal

acquired angio-oedema angio-oedema plastic syndrome and acute myeloid which is not inherited or present at birth, leukaemia associated with t(5;12)(q31;p13) usually caused by an acquired deficiency actins an evolutionarily conserved of C1 inhibitor; it can be an autoimmune family of intracellular proteins, whose condition or consequent on a low grade genes exist in multiple copies in all spe- B-cell neoplasm cies studied; actin molecules polymerize acquired immune deficiency syndrome into intracellular microfilaments that (AIDS) an acquired cell-mediated im- are involved in muscle contraction, mune deficiency syndrome, consequent cell motility and organelle transport; on marked reduction of CD4+ T lympho- immunohistochemical demonstration cytes resulting from HIV infection of actin is useful in the diagnosis of acquired immunity adaptive immunity rhabdomyosarcoma that is altered by exposure to antigens, activated partial thromboplastin dependent on antigen-presenting cells, T time (aPTT) a coagulation test in lymphocytes and B lymphocytes which a contact activator, a partial acquired Pelger–Huët anomaly thromboplastin and calcium are added to acquired hypolobulation of neutrophils plasma with the clotting time then being or other granulocytes, usually indicat- recorded; a test of the intrinsic pathway of ive of myelodysplastic syndrome or acute coagulation (see Fig. 17, p. 77) myeloid leukaemia; the cytological fea- activated protein C resistance resis- tures resemble those of the inherited tance to the anticoagulant effect of Pelger–Huët anomaly activated protein C, often caused by acrocentric having the centromere near inheritance of a variant of factor V, factor one end V Leiden (see naturally occurring antico- ACS2 a gene, Acyl-CoA Synthetase 2, agulants) encoding acyl-CoA synthetase 2, gene actuarial survival an estimate of median map locus 5q31 which contributes to an survival made while many patients are ETV6-ACS2 fusion gene in myelodys- still alive HAE-A 01/13/2005 05:09PM Page 7

acute leukaemia 7

Table 2 WHO criteria for the diagnosis of biphenotypic leukaemia.

Score B lineage T lineage Myeloid

2 cCD79a CD3 (c or Sm) MPO cIgM anti-TCR (αβ or γδ) cCD22 1 CD19 CD2 CD117 CD10 CD5 CD13 CD20 CD8 CD33 CD10 CD65 0.5 TdT TdT CD14 CD24 CD7 CD15 CD1a CD64 If > 2 points is scored for both myeloid and one of the lymphoid lineages the case is classiﬁed as biphenotypic; in the original EGIL recommendations CD117 scored 0.5 rather than 1

c, cytoplasmic; CD, cluster of differentiation; Ig, immunoglobulin; MPO, myeloperoxidase; Sm, surface membrane; TdT, terminal deoxynucleotidyl transferase.

Table 3 A simpliﬁed explanation of the French-American-British (FAB) classiﬁcation of acute myeloid leukaemia (AML).

FAB designation Description

M0 AML with minimal evidence of myeloid differentiation M1 AML with granulocytic differentiation but little maturation M2 AML with granulocytic differentiation and maturation M3 and M3 variant Acute hypergranular promyelocytic leukaemia and the hypogranular or microgranular variant form M4 AML with both granulocytic and monocytic differentiation M5 AML with monocytic differentiation, either without maturation (M5a or acute monoblastic leukaemia) or with maturation (M5b or acute monocytic leukaemia) M6 AML with at least half the bone marrow cells being erythroblasts M7 Acute megakaryoblastic leukaemia

acute basophilic leukaemia an acute erythroid differentiation; the FAB myeloid leukaemia with prominent M6 category of AML (Table 3, see also basophilic differentiation Table 4) acute biphenotypic leukaemia an acute hypergranular promyelocytic acute leukaemia in which there is both leukaemia an acute myeloid myeloid and lymphoid differentiation, leukaemia characterized by leukaemic deﬁned in the WHO classiﬁcation as cells that are abnormal hypergranular shown in Table 2 promyelocytes, the FAB M3 category of acute eosinophilic leukaemia an AML (see Tables 3 and 4) acute myeloid leukaemia with prominent acute leukaemia a leukaemia that, if eosinophilic differentiation untreated, leads to death in weeks or acute erythroleukaemia an acute months; a leukaemia characterized by myeloid leukaemia with prominent continued proliferation with a failure of HAE-A 01/13/2005 05:09PM Page 8

8 acute lymphoblastic leukaemia (ALL)

Table 4 The WHO classiﬁcation of acute myeloid leukaemia (AML).

Acute myeloid leukaemia with recurrent genetic abnormalities* AML with t(8; 21)(q22;q22)/AML1-ETO fusion AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16; 15)(p13;q22)/CBFB-MYH11 fusion Acute promyelocytic leukaemia with t(15; 17)(q22;q12)/PML-RARA fusion, and variants AML with 11q23 rearrangement and MLL abnormality AML with multilineage dysplasia† Following a myelodysplastic syndrome or a myelodysplastic/myeloproliferative syndrome Without antecedent myelodysplastic syndrome Therapy-related AML and myelodysplastic syndrome Alkylating agent-related Topoisomerase II-inhibitor-related Other types AML not otherwise categorized AML, minimally differentiated (resembles FAB M0) AML without maturation (resembles FAB M1) AML with maturation (resembles FAB M2) Acute myelomonocytic leukaemia (resembles FAB M4) Acute monoblastic and acute monocytic leukaemia (resembles FAB M5a, M5b) Acute erythroid leukaemia Erythroleukaemia (resembles FAB M6) Pure erythroid leukaemia Acute megakaryoblastic leukaemia (resembles FAB M7) Acute basophilic leukaemia Acute panmyelosis with myeloﬁbrosis Myeloid sarcoma (granulocytic or monocytic)

* Therapy-related cases may be noted to have one of these abnormalities but are assigned to the category of therapy-related AML. † Deﬁned as having at least 50% of cells dysplastic in at least 2 lineages.

differentiation so that the dominant cell is monly but not always of megakaryocyte a primitive cell referred to as a blast cell lineage acute lymphoblastic leukaemia (ALL) acute myeloid leukaemia (AML) an an acute leukaemia in which the predomin- acute leukaemia in which leukaemic ant cell is a lymphoblast of T or B lineage cells belong to any myeloid lineage, i.e. acute monoblastic leukaemia an granulocytic, monocytic, erythroid or acute myeloid leukaemia in which the megakaryocyte lineages, defined in the dominant cell is a monoblast, the FAB WHO classification as a haematological M5a category of AML (see Tables 3 neoplasm with at least 20% blast cells in and 4) the peripheral blood or bone marrow or acute monocytic leukaemia an acute with a lower percentage of blast cells if myeloid leukaemia in which the leukaemic there is one of three specified chromo- cells are mainly promonocytes and mono- somal rearrangements—t(8;21), inv(16) cytes but with at least 20 or 30% of or t(16;16); AML is further classified as peripheral blood or bone marrow cells shown in Table 4 being blast cells; the FAB M5b category acute myelomonocytic leukaemia of AML (see Tables 3 and 4) (AMML) an acute myeloid leukaemia acute myelofibrosis acute myeloid in which there is both granulocytic and leukaemia with reactive bone marrow monocytic differentiation, the FAB M4 fibrosis; the leukaemic cells are com- category of AML (see Tables 3 and 4) HAE-A 01/13/2005 05:09PM Page 9

AF1q 9

acute non-lymphoblastic leukaemia adenosine triphosphate (ATP) the (ANLL) an alternative designation of nucleotide adenosine, with three attached acute myeloid leukaemia, mainly used in phosphate moieties; an important store the USA of energy acute phase reactant one of a number adhesion the process of becoming of plasma proteins that rise in concentra- closely attached to something else tion in response to acute inflammation adhesion molecule a molecule that or tissue injury, enhancing resistance to promotes adhesion of cells to each other infection and promoting tissue repair adjuvant a substance that non-specifically acute phase reaction an acute systemic enhances antigen-specific immune responses response to infection or inflammation, in ADP adenosine diphosphate which there is a fall in serum albumin, adrenal gland an endocrine gland sited transferrin and iron and a rise in other at the upper pole of the kidney proteins including C-reactive protein, adrenaline see epinephrine serum amyloid A protein, factor VIII, Adriamycin a trade name for doxoru- fibrinogen and α2 macroglobulin bicin, an anthracycline used in the treat- ADA the gene on 20q that encodes adeno- ment of lymphomas and carcinomas sine deaminase, deficiency of which can adult haemoglobin haemoglobin A cause severe combined immunodeficiency adult T-cell leukaemia/lymphoma ADAMTS13 a gene at 9q34, encoding (ATLL) a subacute neoplasm of T a disintegrin-like metalloprotease with lymphocytes which may have either a thrombospondin type 1 motif, 13, also leukaemic or a lymphomatous presenta- known as von Willebrand’s factor- tion; preceding infection by the human cleaving protease, mutation of which T-cell lymphotropic virus I (HTLV-I) is an can cause familial thrombotic throm- essential aetiological factor bocytopenic purpura AE1 a gene, gene map locus 17q21-q22, ADCC antibody-dependent cellular cyto- encoding Solute Carrier family 4, Anion toxicity exchanger, member 1 (SLC4A1) also add a cytogenetic abbreviation indicating known as the Anion Exchanger 1 and additional material of unknown origin band 3 protein, a component of the Addisonian anaemia see pernicious red cell membrane (see Fig. 64, p. 199); anaemia mutation can result in hereditary sphero- Addison’s disease an illness resulting cytosis, hereditary elliptocytosis or South- from chronic failure of the adrenal glands east Asian ovalocytosis; band 3 carries the addresin a tissue-specific adhesion diego blood group antigens molecule AF1p a gene, ALL1 Fusion gene from adenine a purine base that is a com- chromosome 1p, also known as EPS15— ponent of both DNA and RNA, pairs Epidermal growth factor receptor path- with thymine way Substrate-15, gene map locus 1p32; adenocarcinoma carcinoma showing AF1p encodes a phosphorylated protein some features of differentiation to glan- that is a constitutive component of clathrin- dular structures coated pits and is required for clathrin- adenoma a benign tumour of glandular dependent endocytosis; it contributes to tissue the MLL-AF1p fusion gene in some cases adenosine deaminase an enzyme that of M5 acute myeloid leukaemia catalyses the conversion of adenosine to AF1q a gene, ALL1 Fusion gene from inosine; a deficiency can cause severe chromosome 1q, gene map locus 1q21, combined immunodeficiency which contributes to the MLL-AF1q adenosine diphosphate (ADP) the fusion gene in some cases of M4 acute nucleotide adenosine, with two attached myeloid leukaemia; AF1q encodes a phosphate moieties; a store of energy; a nuclear protein, the expression of which platelet agonist is usually restricted to the thymus HAE-A 01/13/2005 05:09PM Page 10

10 AF3p21

AF3p21 a gene, ALL1 Fusion gene AF7p15 a gene, ALL1 Fusion gene from from chromosome 3p21, also known as chromosome 7p15, gene map locus 7p15, SPIN90—SH3 Protein Interacting with encodes a novel protein with no known Nck, 90-KD; gene map locus 3p21, homologies located in the intron of 3′ encoding an SH3 adapter protein that is hydroxybutyrate dehydrogenase; con- normally expressed in cardiomyocytes; tributed to an ETV6-AF7p15 fusion gene was found to be fused with the MLL in a patient with acute myeloid leukaemia gene in a patient with therapy-related associated with t(7;12)(p15;p13) M5 acute myeloid leukaemia associated AF9 a gene, ALL1 Fused gene from chro- with t(3;11)(p21;q23) mosome 9; also known as MLLT3— AF4 a gene, ALL1 Fusion gene from Myeloid/Lymphoid or Mixed Lineage chromosome 4, also known as MLLT2— Leukaemia, translocated to, 3; gene map Myeloid/Lymphoid or Mixed Lineage locus 9p21; encodes a putative nuclear Leukaemia, Translocated to, 2, gene map protein; AF9 contributes to the MLL- locus 4q21, encodes a putative transcrip- AF9 fusion gene in acute myeloid leuk- tion factor widely expressed in normal aemia or, less often, acute lymphoblastic tissues; AF4 contributes to the MLL-AF4 leukaemia, associated with t(9;11)(p21- fusion gene in t(4;11)(q21;q23) associ- 22;q23) ated with acute lymphoblastic leukaemia, AF9q34 a gene, ALL1 Fused gene from acute myeloid leukaemia and acute chromosome 9q34; gene map locus 9q34, biphenotypic leukaemia predicted to encode a RAS GTPase- AF5q31 a gene, ALL1 Fusion gene from activating protein; AF9q34 contributed chromosome 5q31, gene map locus 5q31, to an MLL-AF9q34 fusion gene in a case encodes a homologue of AF4, contribu- of acute myeloid leukaemia associated ted to an MLL-AF5q31 fusion gene in an with t(9;11)(q34;q23) infant with pro-B acute lymphoblastic AF10 a gene, ALL1 Fused gene from leukaemia and ins(5;11)(q31;q13q23) chromosome 10, gene map locus 10p12; and an MLL-AF5q31 fusion in other encodes a widely expressed leucine zipper/ infants with acute lymphoblastic zinc ﬁnger protein; AF10 contributes to: leukaemia • the MLL-AF10 fusion gene in AF6q21 a gene, ALL1 Fusion gene t(10;11)(p12;q23) associated with M5 from chromosome 6q21, also known acute myeloid leukaemia and acute as FKHRL1—Forkhead in Rhabdo- lymphoblastic leukaemia; myosarcoma-Like 1, gene map locus •a CALM-AF10 fusion gene in acute 6q21; encodes a transcription factor myeloid leukaemia of the forkhead family; contributes to AF15q14 a gene, ALL1 Fusion gene the MLL-AF6q21 fusion gene in acute from chromosome 15q14, gene map locus myeloid leukaemia associated with 15q14, encoding a protein with no known t(6;11)(q27;q23) homologies, that contributed to a MLL- AF6q27 a gene, ALL1 Fusion gene from AF15q14 fusion gene in a patient with chromosome 6q27, also known as acute myeloid leukaemia associated with MLLT4—Myeloid/Lymphoid or Mixed t(11;15)(q23;q14) Lineage Leukaemia, Translocated to, 4; AF17 a gene, ALL1 Fusion gene from gene map locus 6q27, encodes a widely chromosome 17; also known as expressed normal component of tight MLLT6—Myeloid/Lymphoid or Mixed and adherens junctions, which has been Lineage Leukaemia, Translocated to, shown to bind RAS; contributes to the 6; gene map locus 17q21; encodes a MLL-AF6q27 fusion gene in M5 acute zinc ﬁnger/leucine zipper protein sim- myeloid leukaemia associated with ilar to AF10; contributes to the MLL- t(6;11)(q27;q23); the normal gene pro- AF17 fusion gene in t(11;17)(q23;q21) duct is cytoplasmic whereas the fusion associated with M5 acute myeloid gene product is nuclear leukaemia HAE-A 01/13/2005 05:09PM Page 11

ALK 11

AFB acid-fast bacillus as PKB—Protein Kinase B, Rac serine/ affinity chromatography separation threonine protein kinase; gene map of proteins by means of differences in locus 14q32.3; encodes a widely expressed affinity for lectins, monoclonal antibod- serine/threonine kinase, which is activ- ies or other proteins ated by a variety of mitogenic signals and affinity selection the process by which which provides a survival signal protect- germinal centre B cells that produce high ing from apoptosis; the Akt1 protein affinity antibodies become memory cells physically interacts with the product of or plasma cells while other B cells suffer TCL1, which mediates its translocation apoptosis to the nucleus; akt1 activity is elevated in afibrinogenaemia an inherited, auto- several human tumours somal recessive, severe reduction or ALAS1 also known as ALASn, a gene, absence of plasma fibrinogen gene map locus 3p21, encoding the ubiq- AFX a gene, ALL1 Fusion gene from uitously expressed δ-amino laevulinate chromosome X, also known as synthase 1 MLLT7—Myeloid/Lymphoid or Mixed ALAS2 an erythroid-specific gene, gene Lineage Leukaemia, Translocated to, map locus Xp11.12, also known as 7; gene map locus Xq13; encodes a ALASe, encoding δ-amino laevulinate widely expressed forkhead transcrip- synthase 2, the enzyme responsible for the tion factor; contributes to the MLL- first step in haem synthesis (see Fig. 34, AFX fusion gene in T-lineage acute p. 116) lymphoblastic leukaemia associated Albers-Schönberg disease see osteo- with t(X;11)(q13;q23) petrosis agammaglobulinaemia a severe reduc- Alder–Reilly anomaly a congenital tion or absence of serum immunoglob- abnormality of granulocytes character- ulin (see congenital autosomal recessive ized by abnormally heavy staining of agammaglobulinaemia and X-linked reces- granules; it may occur as an isolated sive agammaglobulinaemia) defect or as a manifestation of a serious agar a colloid obtained from certain inherited metabolic disease algae, used for electrophoresis, e.g. as aldolase an enzyme in the erythrocyte citrate agar glycolytic pathway (see Fig. 33, p. 113) agarose a neutral fraction of agar, used aleukaemic leukaemia leukaemia occur- for electrophoresis ring without a rise in the peripheral blood agglutination clumping together of white cell count cells, particularly erythrocytes algorithm a step by step decision- agglutinin an antibody that causes making process agglutination of erythrocytes ALIP abnormal localization of immature aggregation sticking together, particu- precursors larly of platelets ALK a gene, Anaplastic Lymphoma agnogenic myeloid metaplasia an Kinase; gene map locus 2p23; encodes the alternative designation of idiopathic transmembrane receptor tyrosine kinase myelofibrosis ALK (CD246), a member of the Ltk agonist a molecule having a specific (Leukocyte Tyrosine Kinase) family, stimulatory effect which is normally expressed by scattered agranulocytosis (i) acute drug-induced cells in the nervous system, gut and testis; immune destruction of neutrophils lead- ALK is involved in a variety of transloca- ing to neutropenic sepsis (ii) severe neu- tions associated with T-lineage anaplastic tropenia of other origin, e.g. congenital large cell lymphoma: ALK: AIDS acquired immune deficiency syndrome • contributes to the NPM-ALK fusion AILD angioimmunoblastic lymphadenopathy gene in the majority of cases of anaplastic AKT1 a gene, v-akt murine thymoma large cell lymphoma associated with viral oncogene homologue 1, also known t(2;5)(p23;q35) HAE-A 01/13/2005 05:09PM Page 12

12 alkaline phosphatase

• is cryptically inserted in the region of in the plasma and expressed in various the NPM gene in a minority of cases of tissues or cells including bone, liver and anaplastic large cell lymphoma neutrophils • contributes to the TPM3-ALK alkaline phosphatase-anti-alkaline fusion gene in the minority of cases phosphatase (APAAP) technique of anaplastic large cell lymphoma a technique for identifying antigens by with t(1;2)(q25;p23)—also described as means of antibodies linked to alkaline t(1;2)(q21;p23) and in inflammatory phosphatase myofibroblastic tumours alkalosis having a blood pH above 7.45 • contributes to ATIC-ALK fusion gene alkylating agent a cytotoxic drug which in the minority of cases of anaplastic cross-links strands of DNA by means of large cell lymphoma with a cryptic alkyl groups inv(2)(p23q35) allele alternative forms of a DNA • contributes to the RanBP2-ALK sequence occupying a given chromo- fusion gene in inflammatory myofibrob- somal locus, e.g. βS is an allele of βA; lastic tumours with t(2;2)(p23;q11-13) or may refer to a non-coding as well as a inv(2)(p23q11-13) coding sequence • contributes to one of two TFG-ALK allele-specific oligonucleotide an

fusion genes (TFG-ALKS and TFG- oligonucleotide that is specific for one ALKL) in occasional cases of anaplastic allele of a gene, permitting it to be large cell lymphoma associated with specifically amplified by PCR t(2;3)(p23;q21) allele-specific oligonucleotide • is likely to be rearranged in hybridization (ASO hybridization) t(2;13)(p23;q34) associated with ana- a PCR technique for identifying specific plastic large cell lymphoma alleles of a gene by the use of allele- • contributes to the CLTC-ALK specific primers fusion gene in a minority of cases of allele-specific polymerase chain reac- anaplastic large cell lymphoma pro- tion see allele-specific oligonucleotide bably associated with t(2;17)(p23;q23), hybridization not t(2;22)(p23;q11.2), and in inflammat- allelic exclusion the process by which ory myofibroblastic tumours (note: the further rearrangements of immuno- designation CLTCL for the partner gene globulin or T-cell receptor genes are is wrong) prevented once a functional rearrange- • contributed to a TPM4-ALK fusion ment has been made during B- or gene in a case of large cell anaplastic T-cell development; ensures that B and lymphoma with NK phenotype asso- T cells make only one type of antigen ciated with t(2;19)(p23;p13) and con- receptor tributes to the same fusion gene in allergen a hapten or antigen capable of inflammatory myofibroblastic tumours giving rise to allergic responses with t(2;19)(p23;p13.1) allergy an acquired inappropriate • contributes to a moesin-ALK specific immune reactivity to a normally fusion gene, probably resulting from harmless environmental antigen, often t(X;2)(q11;p23), in large cell anaplastic IgE mediated lymphoma alloantibody an antibody recognizing Full length ALK is expressed in neuro- antigens on the cells of a genetically blastomas, rare cases of rhabdomyosar- different individual coma and rare cases of IgA-positive alloantigen an antigen expressed on immunoblastic lymphoma tissues of another genetically different alkaline phosphatase this is a generic individual term for an enzyme that works optim- allogeneic genetically different from an ally at alkaline pH to release phosphate individual; relating to any other person groups from complex molecules; present except an identical twin HAE-A 01/13/2005 05:09PM Page 13

AML1 13

allograft a transplant from a non- poiesis and regulates several genes e.g. identical individual those encoding myeloperoxidase, CD13, alloimmune haemolytic anaemia GM-CSF, M-CSF receptor, neutrophil haemolytic anaemia resulting from elastase, IL3 and the T-cell receptor alloantibodies, e.g. caused by transplacen- enhancer: tal passage of antibodies or transfusion of • part of AML1 fuses with part of blood containing alloantibodies the ETO gene at 8q22 in M2 acute alloimmunization the development of myeloid leukaemia associated with immune responses to alloantigens t(8;21)(q22;q22), forming AML1-ETO; all-trans-retinoic acid (ATRA) a dif- AML1-ETO appear to act as a dominant ferentiating agent used in the treatment negative inhibitor of AML1 of M3 AML • part of the EAP, EVI1 and MDS1 alopecia loss of hair genes at 3q26 in t(3;21)(q26;q22) in asso- Alport’s syndrome an inherited syn- ciation with acute myeloid leukaemia drome characterized by renal failure and and blast transformation of myelopro- deafness; the classic pattern of inherit- liferative disorders, forming AML1- ance is autosomal dominant but auto- EAP, AML1-EVI1 and AML-MDS1 somal recessive forms, resulting from • part of ETV6 to form a fusion gene, mutations in either the basement mem- ETV6-AML1 (TEL-AML1), detected brane collagen alpha-3 or alpha-4 genes in about 30% of cases of acute lymph- (COLA3, COLA4), and an X-linked oblastic leukaemia, associated with a form, resulting from mutations in the cryptic t(12;21)(p13;q22) basement membrane collagen alpha-5 • part of MTG16 to form a fusion gene (COLA5) are known; when there is gene, AML1-MTG16, mainly in sec- also thrombocytopenia the designation ondary acute myeloid leukaemia/ Epstein’s syndrome is used, this syndrome myelodysplastic syndrome associated resulting from a mutation in the non- with t(16;21)(q24;q22) muscle myosin heavy chain 9 gene • part of USP25 to form an AML1- (NMMHC-IIA or MYH9) at 22q11-13 USP25 in myelodysplastic syndrome (or 22q12.3-q13.2) • AML1 has also been found to be alternative pathway of complement rearranged in the following transloca- activation complement activation tions associated mainly with secondary initiated by binding of complement myelodysplastic syndromes (following component C3b to bacterial cell walls cytotoxic chemotherapy or irradiation) (see complement system and Fig. 20, p. 81) or acute myeloid leukaemia ALX3 a homeobox gene, Aristaless-Like t(1;21)(p36;q22) (irradiation associated) homeobox 3, gene map locus 1p21-p13; t(5;21)(q13;q22) expressed by pancreatic beta cells, which t(12;21)(q24;q22) is hypermethylated in neuroblastoma t(14;21)(q22;q22) AML acute myeloid leukaemia t(15;21)(q22;q22) AML1 a gene, Acute Myeloid Leukaemia t(18;21)(q21)(q22) (irradiation associated) 1, approved name is RUNX1—runt- t(19;21)(q13.4;q22) (irradiation associated) related transcription factor 1; also known An autosomal dominant familial dis- as CBFA2—Core-Binding Factor, runt order characterized by thrombocytope- domain, Alpha subunit 2; gene map locus nia and platelet function defects with a 21q22; encodes one of a family of runt- propensity to acute myeloid leukaemia domain-containing proteins which asso- has been associated with mis-sense muta- ciate with a non-DNA binding protein tions in the AML1 gene CBFβ, to form one of the heterodimeric Point mutations can occur in AML1 transcription factors, known as the core in myelodysplastic syndromes with the binding factors (CBFs); the AML1/CBFβ mutant gene being a dominant negative complex is required for normal haemo- inhibitor of wild-type AML1 HAE-A 01/13/2005 05:09PM Page 14

14 AMML

Figure 6 Mitosis. The process of mitosis, for clarity showing only four of the 46 chromosomes. Cells that are not actively dividing are in interphase, interphase having G1, S and G2 phases (see Figure 15, p. 71). It is during the S phase that DNA replication occurs, with each chromosome being replicated so that it is composed of two identical daughter chromatids. Mitosis itself has ﬁve phases: (a) in prophase, the chromosomes condense and become visible although the sister chromatids—joined at the centromere—remain closely associated and are not visible; the nuclear membrane dissolves and the centriole divides, moving towards the two poles of the cell; the polar mitotic spindle starts to form from each centriole; during prometaphase (not illustrated) the equatorial spindle develops and the two chromatids become visible; (b) in metaphase, the chromosomes—each composed of two chromatids—align, at the equator of the cell, on the mitotic spindle to which they are attached by their centromeres; (c) in anaphase, the centromeres divide so that the two chromatids are detached from each other and can be pulled toward the two poles of the cell by contraction of the spindle ﬁbres; (d) in telophase, the chromosomes re-condense and the nuclear membrane re-forms around each cluster of chromosomes; the cytoplasm narrows at the equator of the cell and the cell then divides

Prophase Metaphase Anaphase Telophase

Biallelic point mutations have been pleated sheets); one of the many causes is an associated with acute myeloid leukaemia overt or occult plasma cell dyscrasia giving with acquired trisomy 21 rise to light chain-associated amyloidosis AML1 may be amplified in acute anabolism see metabolism myeloid leukaemia (by a segmental ANAE alpha naphthyl acetate esterase, jumping translocation) and in acute one of the non-specific esterases lymphoblastic leukaemia anaemia a reduction in the haemoglobin AMML acute myelomonocytic leukaemia concentration in the blood, in comparison amplification a process of production with what would be found in a normal of multiple copies of DNA sequences individual of the same age and gender in vitro (e.g. by PCR) or the occurrence anaphase the fourth of five phases of of multiple copies of a gene in a cell mitosis in which the centromere divides (e.g. proto-oncogenes may be amplified in and the two chromatids move to either tumour cells) end of the cell (Fig. 6) amplification-refractory mutation anaphylaxis a life-threatening systemic system (ARMS) a PCR method in response to an allergen, resulting from the which primers amplify only a specific release of histamine and other pharmaco- mutated allele logical mediators, in which severe hypo- amyloid a variety of abnormal proteins tension and bronchial constriction are derived from different precursor proteins prominent elements but all characterized by insoluble fibrils anaplastic a description of cells, the with a specific structure—anti-parallel maturation of which shows little re- β-pleated sheets with strands arranged semblance to that of normal cells of the perpendicularly to the fibre long axis same lineage amyloidosis a heterogeneous group of anaplastic large cell lymphoma a disorders in which there is deposition in high grade T-cell lymphoma associated the tissues of a waxy starch-like glyco- with t(2;5) or related translocation (see protein with a distinctive structure (beta Table 11, p. 153) HAE-A 01/13/2005 05:09PM Page 15

antigen 15

ANBE alpha naphthyl butyrate esterase ANK1 a gene, gene map locus 8p11.2, ANCA anti-neutrophil cytoplasmic encoding ankyrin, a component of the red antibodies cell membrane; mutation can result in anergy immunological unresponsiveness hereditary spherocytosis to antigenic challenge, particularly of T ankyrin a protein of the red cell mem- cells brane (see Fig. 64, p. 199) aneuploid having a chromosome num- ANLL acute non-lymphoblastic leukaemia ber that is not 46 nor a multiple nor half anomaly an abnormality, usually inher- of 46 ited or developmental, affecting a chromo- aneuploidy presence of a clone of cells some, cell, tissue, organ or part of the body with a number of chromosomes which is anorexia loss of appetite not 46 nor a multiple nor half of 46 anorexia nervosa a psychogenic illness aneurysm a localized dilation of a blood in which inadequate intake of calories vessel leads to severe weight loss; can cause pan- angiogenesis formation of capillar- cytopenia, acanthocytosis and gelatinous ies and post-capillary venules from pre- transformation of the bone marrow existing vessels antagonist a molecule which counter- angiogram a radiograph of a blood vessel acts the effect of another type of molecule after contrast medium has been injected anthracycline a group of anti-cancer angioimmunoblastic lymphadeno- antibiotics including daunorubicin, pathy (AILD) an immune disorder doxorubicin and epirubicin characterized by fever, lymphadenopathy antibiotic a molecule synthesized by a and hypergammaglobulinaemia; in many living organism, e.g. a fungus, which if not all cases there is an occult T-cell interferes with the proliferation, growth neoplasm or differentiation of other organisms angioimmunoblastic lymphadenopa- or their constituent cells; antibiotics in thy-like (AILD-like) lymphoma a T- clinical use include those directed at cell neoplasm characterized by reactive other micro-organisms and those used for inflammatory changes in involved lymph anti-cancer chemotherapy nodes and systemic manifestation such antibody an immunoglobulin, a protein as fever and autoimmune disease (see produced by a plasma cell, which recogn- Table 11, p. 153) izes and combines with an antigen angio-oedema deep mucocutaneous antibody-dependent cellular cytotox- oedema caused by release of inflammat- icity (ADCC) killing that is mediated ory cytokines not adequately opposed by a cell, such as a natural killer cell, that by C1 inhibitor; can occur as an inherited has Fc receptors and thus can bind to an or acquired abnormality antibody that has already recognized a angioplasty reconstruction or dilation cellular antigen of a vessel, usually by minimally invasive anticoagulant a substance that inhibits methods blood clotting, either in vitro or in vivo angular cheilosis angular stomatitis, antifibrinolytic agent a substance cracks at the corner of the mouth, a which inhibits fibrinolysis feature of iron deficiency antigen a molecule recognized by a angular stomatitis cracks at the corner specialized structure on the surface mem- of the mouth, a feature of iron deficiency brane of a T or B lymphocyte that has the anion a negatively charged ion potential to evoke an immune response; anisochromasia increased variation of large complex antigens are immunogenic staining from one erythrocyte to another, and are therefore designated immuno- reflecting varying haemoglobinization of gens; they are capable of eliciting a erythrocytes specific immune response from either B anisocytosis increased variation in size or T lymphocytes, giving rise to humoral from one erythrocyte to another and cell-mediated immunity respectively HAE-A 01/13/2005 05:09PM Page 16

16 antigenic drift

antigenic drift a slight antigenic change antithrombin a serpin, an inhibitor of in a micro-organism, which occurs over thrombin and of activated factors XII, XI, an extended period of time as a result of a IX and X (see Fig. 27, p. 103); this term gradual accumulation of mutations now usually refers to the protein that was antigenic shift a major, usually sudden, previously designated antithrombin III, antigenic change in a virus, brought encoded by the AT3 gene; its anti- about either by genetic exchanges between coagulant effect is greatly increased by related viruses or by exon/whole gene the presence of heparin; 1 in 2000–5000 of shuffling, both mechanisms represent- the Caucasian population have an inher- ing examples of unequal crossing over ited, autosomally dominant, antithrombin between paired chromosomes; the latter deficiency which is associated with signi- mechanism is much more usual (e.g. in ficant thrombophilia the case of the influenza virus) anuria failure to produce urine antigen-presenting cell a specialized API2 a gene, Apoptosis Inhibitor 2, cell, e.g. Langerhans cell, dendritic cell, also known as BIRC3—Baculoviral IAP macrophage or activated B cell, with the Repeat-Containing protein 3, gene map function of presenting antigen, in an locus 11q21; encodes an inhibitor of apo- HLA type II context, to a helper T cell ptosis present in normal lymphoid tissue; antiglobulin test (Coombs’ test) a contributes to the AP12-MLT fusion gene test for detection of immunoglobulin or in MALT lymphoma associated with complement components on the surface t(11;18)(q21;q21); in the presence of the of erythrocytes (direct antiglobulin test) fusion gene, there is sequestration of or for detection of an antibody in the BCL10 protein in the nucleus serum capable of binding to erythrocytes APAAP alkaline phosphatase-anti-alkaline (indirect antiglobulin test) phosphatase technique, an immuno- anti-inflammatory agent a drug or cytochemistry technique other agent which reduces the body’s APC a gene, Adenomatous Polyposis of inflammatory responses the Colon, gene map locus 5q21; encodes antimetabolite a drug which interferes a large multidomain protein which with the participation of normal meta- interacts with the cytoskeleton and com- bolites such as folic acid, purines or ponents of the wnt/β-catenin signalling pyrimidines, in metabolic pathways system; often regarded as the archetypal anti-neutrophil cytoplasmic antibod- tumour suppressor gene, somatic muta- ies (ANCA) autoantibodies character- tions are seen in the majority of sporadic istic of Wegener’s granulomatosis colorectal tumours, and germline muta- antiphospholipid syndrome a syn- tions in APC are responsible for familial drome including a thrombotic tendency— adenomatous polyposis, an autosomal thrombophilia—and recurrent miscarri- dominant inherited disease ages associated with the presence of apheresis the removal of plasma or antibodies to phospholipid (see also cellular components, e.g. platelets, from primary antiphospholipid syndrome) the circulating blood antiplasmin an inhibitor of plasmin aplasia failure to develop or acquired (see Fig. 27, p. 103); mutation of the absence of a normal tissue or organ gene encoding antiplasmin can produce aplastic anaemia pancytopenia result- an inactive protein with a resultant ing from chronic bone marrow aplasia, haemorrhagic disorder either inherited or acquired antisense oligonucleotides short, apoferritin the protein that binds iron to chemically synthesized, sequence-specific form ferritin; it is an acute phase reactant single-stranded DNA molecules that are apoptosis a process of active or pro- designed to hybridize to, and block the grammed cell death; apoptosis is a phy- translation of, their target mRNAs (see siological process but may be exaggerated also RNA interference) or suppressed in various disease processes HAE-A 01/13/2005 05:09PM Page 17

ATM 17

APT1 previous name for the TNFRSF6 sample by some extraneous influence or gene error in processing aPTT activated partial thromboplastin time arteriole a small thick walled blood AQP1 a gene, gene map locus 7p14, vessel carrying blood away from the alleles of which encode antigens of the heart towards the tissues Colton blood group system, carried on arteritis inflammation of an artery an integral membrane water-transport artery a large thick walled blood vessel protein, aquaporin 1, also known as carrying blood away from the heart Channel-like Integral membrane Protein, towards the tissues 28 RD (CHIP28) arthritis inflammation of joints ardeparin a low molecular weight heparin ASH American Society of Hematology ARF a gene, see also Cyclin-Dependent ASO hybridization allele-specific oligo- Kinase Inhibitor-2A (CDKN2A), gene nucleotide hybridization map locus 9p21; p14ARF is the product of asparaginase an enzyme that destroys the shorter transcript of the CDKN2A the amino acid, asparagine, used in the gene, the product of the longer transcript treatment of acute lymphoblastic being p16INK4a; p14ARF binds to and trig- leukaemia gers the degradation of the MDM2 pro- aspergillosis disease resulting from infec- tein (a p53 inhibitor) leading to cell cycle tion by a fungus of the Aspergillus genus, arrest in both the G1 and G2/M phases; e.g. infection by Aspergillus fumigatus deletion of the exon in the CDKN2A aspirate tissue such as bone marrow, specifying p14ARF is associated with a obtained by suction applied to a needle worse outcome in aggressive non- aspiration process of obtaining an aspi- Hodgkin’s lymphoma rate, e.g. of bone marrow ARG a gene, ABL-Related Gene or ABL2, asplenia absence of the spleen gene map locus 1q25, encodes a tyrosine asplenic having no spleen kinase; contributed to a ETV6-ARG AT3 the gene at 1q24-q25 that encodes fusion gene in a cell line with t(1;12) antithrombin, mutation of which can (q25;p13) occurring as a second event in a lead to thrombophilia patient with M3 acute myeloid leukaemia ataxia telangiectasia a recessively and as a second event in a patient with inherited syndrome, resulting from M4Eo acute myeloid leukaemia mutation of the ATM gene, in which argatroban a thrombin inhibitor, unre- there is cerebellar degeneration, telang- lated to heparin iectasiae, defective cell-mediated immun- ARMS amplification-refractory mutation ity, increased sensitivity to ionizing system radiation and a predisposition to T- ARNT a gene, Aryl hydrocarbon lineage prolymphocytic leukaemia and Receptor Nuclear Translocator, gene other lymphoid neoplasms map locus 1q21, encodes a helix–loop– atheroma deposition of lipid in the walls helix transcription factor which hetero- of arteries dimerizes with the dioxin receptor and ATIC a gene, also known as AICARFT regulates genes encoding components of (5-Aminoimidazole-4-Carboxamide Ri- the cytochrome P450 system; contributed bonucleotide Formyltransferase), gene to an ETV6-ARNT fusion gene in a case map locus 2q35; encodes the enzyme of M2 acute myeloid leukaemia asso- that catalyses the penultimate step in the ciated with t(1;12)(q21;p13) de novo purine biosynthetic pathway; ART4 a gene, gene map locus 12p13.2- contributes to the ATIC-ALK fusion gene p12.1, polymorphism of which lead to in the minority of cases of anaplastic expression of the Dombrock blood group large cell lymphoma with a cryptic antigens inv(2)(p23q35) artefact an abnormality that is intro- ATM a gene, Ataxia-Telangiectasia duced into a tissue or a peripheral blood Mutated, gene map locus 11q22-23; a HAE-A 01/13/2005 05:09PM Page 18

18 atopy

candidate tumour suppressor gene which of infectious mononucleosis or other viral encodes a serine-threonine kinase with a infection; also referred to as ‘atypical phosphatidylinositol-3 kinase domain; mononuclear cell’ ATM is widely expressed but especially atypical mononuclear cell see atypical abundant in brain, skeletal muscle and lymphocyte testis; it has a central role in signalling Auer rod a rod-shaped crystalline struc- pathways activated by DNA damage; ture derived from primary granules, activation of this kinase leads to phos- found in the cytoplasm of cells of granu- phorylation of p53, arresting the cell locytic and, less often, monocytic lineage, cycle and permitting DNA repair or observed in acute myeloid leukaemia and apoptosis; ATM mutations are the cause RAEB-T category of the FAB classific- of ataxia-telangiectasia, a chromosomal ation of myelodysplastic syndromes instability syndrome; also implicated in auto- pertaining to self T-prolymphocytic leukaemia; ATM is autoantibody an antibody directed at often mutated or deleted in mantle cell antigens expressed on the body’s own cells lymphoma, deleted in cases of chronic autocrine stimulation of a cell by a lymphocytic leukaemia with del(11)(q23) molecule secreted by the cell itself, creat- and mutated in a proportion of other ing an ‘autocrine loop’ cases of chronic lymphocytic leukaemia autograft a ‘transplant’ of autologous atopy a hereditary predisposition to IgE- tissue; this term is a misnomer since the mediated disease provoked by common procedure is not a transplant but merely environmental antigens the storage of autologous tissue for sub- ATP adenosine triphosphate sequent return to the same individual ATRA all-trans retinoic acid autohaemolysis test a test for incre- ATRA syndrome a syndrome of fever, ased destruction of erythrocytes suspended pulmonary infiltrates, weight gain, in autologous plasma pleural and pericardial effusions and autoimmune a disease or process in renal failure that can occur when acute which the body mounts a humoral or cell- promyelocytic leukaemia is treated with mediated immune response to autologous all-trans retinoic acid (ATRA) antigens atrophic glossitis inflammation of the autoimmune haemolytic anaemia tongue with atrophy of the papillae, a anaemia caused by autoimmune (antibody- feature of iron deficiency and pernicious mediated) destruction of erythrocytes anaemia autoimmune lymphoproliferative atrophy regression of an organ or tissue syndrome an inherited condition ATRX a gene, gene map locus Xq13.1- characterized by hepatosplenomegaly, q21.2, that encodes an activator of α lymphadenopathy and autoimmune dis- globin genes ease (including autoimmune haemolytic ATRX syndrome a syndrome of mental anaemia and autoimmune thrombocyto- retardation and haemoglobin H disease penia) resulting from mutation in the resulting from loss or mutation of the TNFRSF6 (fas) gene, previously known ATRX gene as APT1 (type 1a), the TNFSFS6 (fas lig- atypical chronic myeloid leukaemia and) gene (type Ib) or the CASP10 (cas- (aCML) a chronic myeloid leukaemia pase gene) (type II); the disease results that differs clinically, haematologically from the failure of apoptosis of lymphoid and at a cytogenetic and molecular cells; diagnostic criteria suggested by the genetic level from Philadelphia-positive NIH are: (i) chronic accumulation of chronic granulocytic leukaemia non-malignant lymphocytes; (ii) increased atypical lymphocyte a lymphocyte T lymphocytes with the immunopheno- which differs cytologically from a normal type αβ+CD4–CD8– and (iii) defective lymphocyte; the term is often applied to in vitro receptor-mediated lymphocyte lymphocytes with features characteristic apoptosis HAE-A 01/13/2005 05:09PM Page 19

autosomal recessive 19

Figure 7 Autosomal dominant inheritance—von Willebrand’s disease. A family tree showing the inheritance of von Willebrand’s disease (loosely based on an actual family) showing autosomal dominant inheritance; the disease is passed from parent to child irrespective of gender with there being a 1 in 2 chance of any child inheriting the condition. Note that only one of non-identical twins in the second generation is affected. For each individual the factor VIII percentage and the bleeding time (in minutes) are given.

I 43% 105% 17m 8m

47% 103% 142% 35% 115% II 1 >20m 6m 5 / 2 m 18m 8m

III 42% 29% 48% 98% 140% 110% 40% 96% 98% 1 19m >20m 18m 7 / 2 m 8m 7m 17m 8m 9m

IV 80% 136% 36% 111% 80% 95% 106% 21% 130% 1 8m 7m >20m 6 / 2 m 8m 8m 7m >20m 7m

Normal male Affected male Normal female Affected female

Figure 8 Autosomal recessive inheritance— autoimmune thrombocytopenic pur- pyruvate kinase deficiency. pura thrombocytopenia caused by auto- Pedigree of a hypothetical family in which a boy (IV1) immune (antibody-mediated) destruction was found to have severe anaemia resulting from of platelets pyruvate kinase deficiency. His parents, III3 and III4, were first cousins. They, two of his grandparents autologous pertaining to an individu- and his great-grandmother were heterozygous al’s own cells or tissues carriers of pyruvate kinase deficiency. This is an autologous stem cell transplantation example of autosomal recessive inheritance in a a misnomer, autologous cells are re- family in which a consanguineous marriage occurred infused but this is not a transplant autophagic vacuole a vacuole in the I cytoplasm of a cell containing material 1 2 derived from the cell itself II autosomal pertaining to an autosome 1 245673 autosomal dominant a form of inheritance in which a single copy of an allele III on an autosome is sufficient to cause an 132 456 alteration in phenotype, either an inher- IV ited characteristic or an inherited disease 1 (Fig. 7) autosomal recessive a form of inherit- Normal male Carrier female ance in which homozygosity (or compound heterozygosity) for an autosomal Normal female Affected male allele is required for a phenotypic effect Carrier male Propositus (Fig. 8) HAE-A 01/13/2005 05:09PM Page 20

20 autosome

autosome a chromosome other than X, over-expressed in chronic granulocytic Y or a mitochondrial chromosome; leukaemia a diploid cell has two copies of each azathioprine an antimetabolite used autosome for immune suppression; which can AXL a gene, Anexelekto (Greek for cause pancytopenia and megaloblastic ‘uncontrolled’), gene map locus 19q13.1- erythropoiesis q13.2, archetypal member of a novel azurophilic taking up basic dyes such as family of receptor tyrosine kinases; the azure dyes; basophilic HAE-B 01/13/2005 05:09PM Page 21

2,3-biphosphoglycerate (2,3-BPG) which are strongly associated with an intermediate in the glycolytic pathway thrombophilia and other features of the that decreases the oxygen affinity of antiphospholipid syndrome haemoglobin, previously known as 2,3- BAC bacterial artificial chromosome diphosphoglycerate (see Fig. 33, p. 113) bacteraemia presence of bacteria in the β chain (i) the beta globin chain that blood stream forms part of haemoglobin A (ii) part of bacterial artificial chromosome (BAC) the αβ T-cell receptor, a surface mem- a bacterial cloning vector capable of brane structure in T lymphocytes which maintaining very large fragments of eukary- permits recognition of antigens otic genomic DNA in E. coli; essential for β error the lack of a statistically genome analysis and mapping significant difference when a real differ- bacterium (plural bacteria) unicellular ence does exist, indicative of inadequate micro-organisms which may be round, power of an experiment or clinical trial rod-shaped, spiral or comma shaped β globin cluster the cluster of genes on babesiosis a disease resulting from chromosome 11 that includes the genes infection by protozoan parasites of the encoding ε, Gγ, Aγ, δ and β globin chains genus Babesia (see Fig. 1) bacillus (plural bacilli) a rod-shaped β globin gene the HBB gene, gene map bacterium locus 11p15.5, encoding the β globin chain B acute lymphoblastic leukaemia (B- β thalassaemia thalassaemia caused by ALL) ALL with cells having a mature mutation or, less often, deletion of a β B-cell immunophenotype, i.e. expressing globin gene leading to reduced beta globin surface membrane immunoglobulin synthesis BAD a protein of the BCL2 family that β thalassaemia intermedia a genetic- is pro-apoptotic because of its ability

ally heterogeneous condition intermed- to sequester BCL2 and BCLXL; binding iate in severity between thalassaemia trait of cytokines, such as interleukin-3, to and thalassaemia major; the severity is their ligands can phosphorylate BAD so very variable but blood transfusions are that it cannot then sequester these anti- not essential for the maintenance of life apoptotic proteins β thalassaemia major a severe transfu- balanced polymorphism the persis- sion-dependent thalassaemic condition tence of a polymorphic allele at a stable resulting from homozygosity or compound frequency from generation to generation, heterozygosity for β thalassaemia usually implies a balance between the β thalassaemia trait a clinically mild beneﬁcial and deleterious effects of the or inapparent thalassaemic abnormal- allele ity, resulting from heterozygosity for β balanced translocation a transloca- thalassaemia tion in which microscopic examination of β 2-glycoprotein I a phospholipid- metaphase spreads discloses neither gain binding protein, a putative naturally nor loss of chromosomal material (Fig. 9, occurring anticoagulant, antibodies to p. 22)

21 HAE-B 01/13/2005 05:09PM Page 22

22 band

Figure 9 A balanced translocation. Two diagrammatic representations of a balanced translocation—t(15;17)(q22;q21); there is exchange of material between two chromosomes with no net gain or loss. The upper ﬁgure shows the two normal and two abnormal chromosomes with their characteristic banding patterns. The short arm (p), long arm (q), centromere, telomeres and the two chromatids that make up a chromosome are also indicated. In the lower diagram chromosome 15 and material derived from it is shown in black and chromosome 17 and material derived from it in white.

Telomere Centromere

q21

q q21 Derivative Normal 17 17 Telomere Two chromatids Normal Derivative 15 15

Normal Derivative 17 17

Normal Derivative 15 15

band a chromosomal region that, after rich domain (RING motif) which is found staining, can be distinguished from in many proteins that regulate cell adjoining regions by appearing darker or growth; implicated in familial breast and lighter (see Fig. 31, p. 110) breast plus ovarian cancer band 3 a red cell membrane protein bare lymphocyte syndrome an (CD233), also known as anion exchanger immune deﬁciency syndrome in which 1, encoded by the AE1 gene at 17q21-q22 lymphocytes are ‘bare’ of either class I or (see Fig. 64, p. 199) class II HLA molecules band cell a late cell of granulocyte lin- bare nucleus a nucleus that has lost its eage with a non-segmented band-shaped cytoplasm, e.g. a mature megakaryocyte nucleus that has shed its cytoplasm as platelets, banding a technique for staining chro- or a cell of any lineage that has lost its mosomes so that bands are apparent (see cytoplasm during spreading of a blood G-banding, Q-banding) or bone marrow ﬁlm BARD1 a gene, BRCA1-Associated Ring Barr body a clumped area of chromatin Domain 1, gene map locus 2q, encodes a representing an inactive X chromosome; pro-apoptotic protein bearing a cysteine- a nuclear drumstick in a neutrophil is HAE-B 01/13/2005 05:09PM Page 23

BCL3 23

equivalent to a Barr body in other patients with splenic lymphoma with somatic cells villous lymphocytes and B-lineage pro- bartonellosis infection by bacteria of lymphocytic leukaemia; rearranged in the genus Bartonella, e.g. infection by parathyroid adenoma and overexpres- Bartonella bacilliformis which is the cause sed in breast cancer and head and neck of Oraya fever cancer base (i) a proton acceptor (ii) a ring- BCL2 a gene, B-Cell Leukaemia/ shaped organic molecule containing lymphoma 2; gene map locus 18q21.3; nitrogen which is a constituent of DNA encodes an inner mitochondrial mem- and RNA; DNA contains four bases— brane protein which can protect cells in adenine, guanine, cytosine and thymine; conditions that would otherwise bring RNA contains four bases—adenine, gua- about apoptosis; the anti-apoptotic activ- nine, cytosine and uracil ity of the BCL2 protein is enhanced by base pair (bp) a pair of speciﬁc bases, phosphorylation, but its precise mechan- e.g. adenine plus thymine, in the comple- ism of action is not known; the archety- mentary strands of the DNA double pal member of a family of genes encoding helix; bp are the basic units for measuring proteins with pro- and anti-apoptotic the length of a DNA sequence functions; the gene is dysregulated in basophil a granulocyte which, on a follicular lymphoma and various other Romanowsky stain, has large purple B-lineage lymphomas (10–20% of B- granules almost obscuring the nucleus lineage large cell lymphomas) when it basophilia (i) increased uptake of basic is brought into proximity to one of dyes such as azure blue or methylene the genes encoding the heavy or light blue, conveying a blue colour to cyto- chains of immunoglobulin: the IGH plasm (ii) an increased basophil count locus in t(14;18)(q32;q21), the κ gene basophilic erythroblast an early ery- in t(2;18)(p12;q21) or the λ gene in throid precursor, derived from a proery- t(18;22)(q21;q11); protection from apo- throblast (see Fig. 25, p. 95) ptosis may lead to an expanded pool of basophilic leukaemia leukaemia with cells subject to secondary genetic events; prominent basophilic differentiation BCL2 is implicated in the majority of basophilic stippling the presence of cases of follicular lymphoma and in 1– evenly dispersed purplish blue dots in the 2% of cases of chronic lymphocytic cytoplasm of erythrocytes, representing leukaemia, the breakpoints in BCL2 in altered ribosomes follicular lymphoma and in chronic BAX a protein that leads to activation of lymphocytic leukaemia being different; caspases and therefore apoptosis BCL2 rearrangement has also been B cell a lymphocyte of B lineage, i.e. a cell observed in patients with clonal B-cell with the potential to differentiate into an proliferation in association with chronic antibody-secreting plasma cell, named hepatitis C infection from the Bursa of Fabritius in the chicken BCL2 a protein, encoded by BCL2, BCL1 a gene, B-Cell Leukaemia/ that sequesters BAX and is therefore lymphoma 1, also known as PRAD1, anti-apoptotic CCND1; gene map locus 11q13, encodes BCL3 a gene, B-Cell Leukaemia/ cyclin D1; cyclins complex with and activ- lymphoma 3, formerly BCL4; gene map ate the p34 (CDC2) protein kinase, and locus 19q13, belongs to a family of genes regulate progress through the cell cycle; that encode inhibitors (IκB proteins) of κ κ dysregulated by proximity to the IGH the transcription factor NF B2; I B pro- locus as a result of the t(11;14)(q13;q32) teins interact with REL/NFκB proteins translocation in the great majority of in unstimulated cells and sequester them patients with mantle cell lymphoma, in the cytoplasm by masking nuclear 20–25% of patients with multiple my- localization signals; on cell stimulation, eloma and a signiﬁcant minority of IκB is degraded, permitting NFκB to HAE-B 01/13/2005 05:09PM Page 24

24 BCL6

translocate to the nucleus and bind to cis- of a worse survival in post-transplant acting sequences that induce gene expres- lymphoproliferative disorder; BCL6 is sion; BCL3 is rearranged, brought into expressed on the neoplastic cells of nodu- juxtaposition to the IGH enhancer and lar lymphocyte predominant Hodgkin’s overexpressed in t(14;19)(q32;q13); this disease and on some cells in a minority translocation is found in less than 1% of of cases of classical Hodgkin’s disease; cases of chronic lymphocytic leukaemia mutations of BCL6 appear to be common and is associated with a young age at pre- in classical Hodgkin’s disease of B-cell sentation and poor prognosis origin but in general these diseases are BCL6 a gene, B-Cell Leukaemia/ not associated with BCL6 expression and lymphoma 6, also known as Zinc Finger BCL6 is therefore unlikely to be relevant protein 51 (ZNF51) and Lymphoma- in pathogenesis; BCL6 contributes to: Associated Zinc ﬁnger gene on chromo- •a TTF-BCL6 fusion gene or promoter some 3 (LAZ3); gene map locus 3q27; exchange between BCL6 and Rho/TTF encodes a zinc ﬁnger transcriptional in non-Hodgkin’s lymphoma with repressor closely related to the Drosophila t(3;4)(q27;p13) ‘tramtrack’ and ‘Broad-complex’ genes; •a SRP20-BCL6 fusion gene in non- BCL6 protein is expressed by normal ger- Hodgkin’s lymphoma with t(3;6)(q27;p21) minal centre B cells (and T cells) but not • an H4-BCL6 fusion gene in non- virgin B cells, post-germinal centre B cells Hodgkin’s lymphoma with t(3;6)(q27;p21) (including memory cells) or plasma cells; • an IKAROS-BCL6 fusion gene in non- BCL6 regulates germinal centre forma- Hodgkin’s lymphoma with t(3;7)(q27;p12) tion and T-cell responses; the BCL6 gene •aBOB1-BCL6 fusion gene in non- is involved in t(3;14)(q27;q32) and in a Hodgkin’s lymphoma with t(3;11)(q27;q23) great variety of other translocations • an LCP1-BCL6 fusion gene in non- which have been associated with 30– Hodgkin’s lymphoma with t(3;13)(q27;q14) 40% of B-lineage large cell lymphomas; 5′ BCL7A a gene, B-Cell Leukaemia/ non-coding point mutations in BCL6 lymphoma 7A, gene map locus 12q24; a leading to increased expression occur in widely expressed gene which encodes a an even larger proportion of B-lineage predicted protein with no discernible large cell lymphomas, in the absence of structural or functional motifs; dys- translocations with a 3q27 breakpoint; regulated by proximity to IGH in high levels of BCL6 expression in diffuse t(12;14)(q24;q32) associated with B-cell large B-cell lymphoma is associated with malignancy a favourable outcome; BCL6 mutations BCL7B a gene, B-Cell Leukaemia/ occur in a proportion of normal B cells lymphoma 7B, gene map locus 7q11.23, a (30–50%) that pass through germinal widely expressed gene which encodes a centres and are also associated with predicted protein with no discernible germinal centre and post-germinal centre structural or functional motifs, closely B-cell neoplasms including follicular related to BCL7A, not as yet implicated lymphoma, MALT-type lymphoma, in any haematological malignancy lymphoplasmacytoid lymphoma, diffuse BCL7C a gene, B-Cell Leukaemia/ large B-cell lymphoma, Burkitt’s lymphoma 7C, gene map locus 16p11, a lymphoma and a subset of B-chronic widely expressed gene which encodes a lymphocytic leukaemia/small lympho- predicted protein with no discernible cytic lymphoma and hairy cell leukaemia; structural or functional motifs; closely BCL6 mutations are associated with related to BCL7A, not as yet implicated large cell transformation of follicular in any haematological malignancy lymphoma; BCL6 mutations are found BCL8 a gene, B-Cell Leukaemia/ in about a quarter of cases of chronic lymphoma 8, gene map locus 15q11-13, lymphocytic leukaemia; BCL6 muta- encodes a predicted protein with no dis- tions have been found to be predictive cernible homologies to other known gene HAE-B 01/13/2005 05:09PM Page 25

BCR 25

products; normally expressed in prostate within the BCL10 gene have been re- and testis but not in lymphoid cells; rear- ported to occur in a variety of cancers but ranged in 3–4% of diffuse large B-cell this may be a cloning artefact lymphomas; probably dysregulated by BCL11A a gene, B-Cell Leukaemia/ proximity to IGH in t(14;15)(q32;q11-13) lymphoma 11A, mouse, homologue of; which is found in less than 1% of cases of also known as evi9; gene map locus 2p13; diffuse large B-cell lymphomas evi9 is a common site for retroviral inte- BCL9 a gene, B-Cell Leukaemia/ gration in murine myeloid leukaemias; lymphoma 9, gene map locus 1q21, encodes an evolutionarily conserved zinc- encodes a predicted protein with no dis- ﬁnger protein with highest expression in cernible homologies to other known gene brain, spleen, and testis; it is brought into products; involved in t(1;14)(q21;q32) in proximity to the IGH enhancer in ‘child- B-lineage acute lymphoblastic leukaemia hood chronic lymphocytic leukaemia’ and other B-cell malignancies in which it is associated with t(2;14)(p13;q32); the dysregulated by proximity to the IGH locus same translocation with dysregulation BCL10 a gene, B-Cell Leukaemia/ of BCL11A is also observed in atyp- lymphoma 10. gene map locus 1p22; ical chronic lymphocytic leukaemia/non- BCL10 is normally ubiquitously expres- Hodgkin’s lymphoma sed at low levels; it encodes a CARD BCL11B a gene, B-Cell Leukaemia/lym- domain-containing pro-apoptotic pro- phoma 11B, also known as CTIP2, gene tein; in addition, normal BCL10 pro- map locus 14q32.1, encodes a protein tein dimerizes with the product of the structurally similar to BCL11A; highly MLT gene and activates the latter’s expressed during normal T-cell differenti- caspase-like domains; this in turn en- ation and is probably responsible for the hances the activation of the transcrip- transcriptional activation of HOX11L2 tion factor NFκB in response to a variety in a quite common t(5;14)(q35;q32) cryp- of antigen receptor induced signals; the tic translocation in T-lineage acute lym- pro-apoptotic activity of BCL10 requ- phoblastic leukaemia; it is expressed in ires intact CARD and carboxyl term- cell lines derived from patients with adult inal domains, whereas NFκB activation T-cell leukaemia/lymphoma requires an intact CARD but not the full- BCLXL a protein that sequesters BAX and length carboxyl terminal domain; re- is therefore anti-apoptotic arranged in t(1;14)(p22;q32) in some cases BCR Breakpoint Cluster Region, gene of high grade MALT lymphoma, high map locus 22q11.21, encodes a widely grade follicle centre cell lymphoma and expressed cytoplasmic protein which has Hodgkin’s disease; t(1;14)(p22;q32) is serine/threonine kinase activity, at least found in about 5% of MALT lymphomas two SH-2 domains and enhances GTPase and in gastric MALT lymphoma muta- activity of p21rac (see RAC1); in addition, tion is predictive of failure of response normal BCR protein is known to interact to antibiotic therapy; in t(1;14)(p22;q32) with the DNA repair protein, XPB; BCR BCL10 is overexpressed following juxta- contributes to: position to the IGH enhancer; carboxy •aBCR-ABL fusion gene, encoding terminus truncations have been reported a tyrosine kinase, as a result of the in several lymphomas independently of t(9;22)(q34;q11) translocation in chronic any cytogenetic changes, such truncated granulocytic leukaemia, a signiﬁcant pro- proteins can continue to activate NFκB portion of cases (particularly adults) with while no longer promoting apoptosis; acute lymphoblastic leukaemia and a in the presence of the t(11;18)(q21;q21) small minority of cases of acute myeloid translocation in gastric MALT lym- leukaemia phoma, which results in the AP12-MLT •a FGFR1-BCR fusion gene in chronic fusion protein, there is sequestration of myeloid leukaemia associated with BCL10 protein in the nucleus; mutations t(8;22)(p11;q11) HAE-B 01/13/2005 05:09PM Page 26

26 BCR-ABL

Figure 10 Bence Jones protein. Demonstration of Bence Jones protein in the urine of a patient with IgG multiple myeloma. Electrophoresis of the urine (lane 5) shows an albumin band and a discrete heavy band early in the gamma region (top). Lanes 1 and 10 are control serum samples. Lanes 2 and 3 show albumin only whereas lanes 6–9 are negative. Immunoﬁxation (bottom) shows that the band is identiﬁed with anti-lambda but not anti-gamma antiserum. It is therefore a lambda Bence Jones protein.

BCR-ABL the fusion gene on chromosome benign ‘not harmful’, a description of 22 formed as a result of t(9;22)(q34;q11), a non-aggressive neoplasm encoding BCR-ABL protein benign lymphoid aggregate an BCR-ABL a non-receptor tyrosine kinase aggregate of lymphocytes present in the encoded by the BCR-ABL fusion gene bone marrow as a reactive phenomenon, BCSH British Committee for Standards in better referred to as a ‘reactive lymphoid Haematology aggregate’ Bence Jones myeloma multiple benign monoclonal gammopathy a myeloma in which the paraprotein syn- very low grade B-lineage lymphoid neo- thesized is a monoclonal light chain plasm with cells secreting small amounts rather than a complete immunoglobulin of a paraprotein; the designation ‘mono- Bence Jones protein a monoclonal clonal gammopathy of undetermined signi- light chain (kappa or lambda) synthe- ﬁcance’ is now preferred sized in multiple myeloma, either as the Bernard–Soulier syndrome an inher- only paraprotein present or together with ited, autosomal recessive, platelet abnor- a monoclonal immunoglobulin; Bence mality characterized by giant platelets Jones protein, as initially described by that do not aggregate normally with ris- Henry Bence Jones, was a protein that tocetin; it can result from mutations in coagulated at 45°C to 55°C but redis- the GPIBA, GP1BB, GPV or GPIX genes solved on heating to a higher tempera- BFU-E burst forming unit-erythroid ture; it is now usually demonstrated bHLH basic helix loop helix; a protein by electrophoresis and immunoﬁxation motif found in certain transcription (Fig. 10) factors which allows binding to a DNA HAE-B 01/13/2005 05:09PM Page 27

boat-shaped cell 27

sequence known as the E box, which is blast cell a primitive cell or haemopoi- found in the regulatory regions of many etic or lymphoid lineage, e.g. a myelo- genes; HLH proteins fall into two blast or a lymphoblast (Fig. 12) classes—Class I HLH proteins, e.g. E2A, blast crisis blast transformation of are widely expressed and are capable of chronic granulocytic leukaemia homodimerization and/or heterodimer- blast transformation the transforma- ization, Class II HLH proteins, e.g. tion of a low grade leukaemia to an acute TAL1, are expressed in a tissue-specific leukaemia, e.g. blast transformation of manner and bind DNA only as het- chronic granulocytic leukaemia erodimers with class I proteins bleeding time the time for which bleed- BHLHB1 a gene, Basic Helix–Loop–Helix ing continues from a standardized skin protein, class B, 1, gene map locus 21q22, puncture or incision, determined by encodes a transcription factor normally platelet number and function only expressed in neural tissues; overex- B lineage a lineage of lymphoid cells that pressed when brought into proximity to differentiate into antibody-synthesizing the TCRAD (αδ) locus in a patient with plasma cells T-lineage acute lymphoblastic leukaemia blood component constituents of associated with t(14;21)(q11.2;q22) blood separated from whole blood bias in the statistical sense, a systematic with minimal manipulation, mainly factor resulting in inaccuracy red cells, platelets or plasma but bile the fluid containing bilirubin and bile also leucocytes, cryoprecipitate and salts secreted by the liver and concen- ‘cryosupernatant’ trated in the gall bladder blood product a biological product pre- bilirubin a pigmented breakdown prod- pared by fractionation or processing of a uct of haemoglobin, produced by macro- blood component, e.g. immunoglobulin, phages and by liver parenchymal cells; in albumin the liver it is conjugated with glucuronic blood tap jargon used to describe an acid prior to excretion in the bile (Fig. 11) attempt at bone marrow aspiration that bioinformatics the study of informa- yields only blood tion content and information flow in bio- Bloom’s syndrome a rare recessively logical systems and processes inherited condition, most common among biopsy the removal of tissue from a living Ashkenazi Jews, characterized by growth person for diagnostic purposes retardation, telangiectatic erythema, photo- biphenotypic a leukaemia with a single sensitivity, immune deficiency, subfer- leukaemic cell population having features tility and an increased risk of cancer, of two lineages—haemopoietic or B or T including leukaemia; Bloom’s syndrome lymphoid, e.g. myeloid and B-lymphoid results from a mutation in the BLM Birbeck granules granules character- gene leading to a deficiency of the BLM istic of Langerhans cells protein, a member of the RecQ family of bite cell an erythrocyte from which a DNA helicases, which associates with Heinz body has been removed by a chromosomes during meiosis; Bloom’s macrophage of the reticuloendothelial syndrome cells show genomic instability system, leading to the formation of a cell with an increased frequency of sister from which a bite appears to have been chromatid exchange and an increased rate taken, a keratocyte of somatic mutation bivalirudin a hirudin derivative, a B lymphocyte a lymphocyte, also thrombin inhibitor known as a B cell, with the potential to Blackfan–Diamond syndrome see mature into an antibody-secreting plasma Diamond–Blackfan syndrome cell (Fig. 13) black water fever acute intravascu- BMT bone marrow transplantation lar haemolysis occurring in falciparum boat-shaped cell a cell the shape of malaria which resembles a boat viewed from HAE-B 01/13/2005 05:09PM Page 28

Figure 11 The results of red cell breakdown. Normal red cell breakdown and intravascular and extravascular haemolysis (not to scale). Red cells at the end of their life span and abnormal or antibody-coated red cells are phagocytosed by macrophages of the reticulo–endothelial system. The haemoglobin of the red cells is degraded to globin, iron and protoporphyrin, the latter then being converted to bilirubin. Unconjugated bilirubin is transported to the liver. In intravascular haemolysis, haemoglobin is released from red cells and binds to plasma haptoglobin. The complexes thus formed are cleared by the parenchymal cells of the liver which degrade haemoglobin and convert protoporphyrin to bilirubin. Bilirubin, whether produced in the liver or transported there, is conjugated to form bilirubin glucuronide. Conjugated bilirubin is excreted in the bile and enters the intestine. Within the intestine, bacteria convert bilirubin to urobilinogen, which is either reabsorbed and excreted in the urine or passes further down the intestinal tract where it is known as stercobilinogen. Extravascular haemolysis, if marked, leads to release of more haemoglobin than can be bound by haptoglobin with the result that free haemoglobin is ﬁltered from the plasma by the kidneys, leading to haemoglobinuria. Some haemoglobin is resorbed by renal tubules and converted to haemosiderin, which later appears in the urine as the renal tubular cells are shed.

Intravascular Normal red cell breakdown haemolysis and extravascular haemolysis

Haemoglobin Haptoglobin Macrophage of reticulo-endothelial system Blood Haemoglobin Methaemalbumin vessel Haem + globin Free haemoglobin Haemoglobin– Amino acids not bound to haptoglobin Iron + protoporphyrin haptoglobin complex Bilirubin

Cleared by parenchymal cells Kidney of liver

Haem + globin

Iron + protoporphyrin

Bilirubin

Bilirubin conjugated to form bilirubin glucuronide Conjugated biliribin Liver (bilirubin glucuronide) Haemoglobinuria, in bile enters intestine later haemosiderinuria

Small intestine

Reabsorbed Kidney

Large intestine Bilirubin Urobilinogen

Faecal urobilinogen Urinary (stercobilinogen) urobilinogen HAE-B 01/13/2005 05:09PM Page 29

bromodomain 29

Figure 12 A lymphoblast. bone marrow fibrosis the deposition A transmission electron micrograph of a of increased amounts of reticulin (retic- lymphoblast from a patient with acute lymphoblastic ulin fibrosis) or reticulin plus collagen leukaemia. There is a high nucleocytoplasmic ratio (collagen fibrosis) in the bone marrow and the nucleus shows little chromatin condensation. bone marrow necrosis the non- selective death of bone marrow cells, e.g. due to an inadequate blood supply for the metabolic needs of the tissue bone marrow transplantation (BMT) the engraftment of haemopoietic stem cells by means of the intravenous infusion of bone marrow cells, either derived from the individual himself (autologous transplantation) or from another individual (allogeneic transplantation) bone scan an imaging technique using a radioactive isotope; increased isotope uptake in areas of increased osteoblast activity causes ‘hot spots’ on the scan; it should be noted that this is not a recommended test for detection of the osteolytic lesions of above, suggestive of the presence of multiple myeloma since these often do not haemoglobin S but not pathognomonic give rise to any abnormality on a bone scan BOB1 a gene, B-cell specific Octomer- borreliosis a disease resulting from infec- Binding transcription factor, also known tion by micro-organisms of the genus as POU2AF1—POU domain, class 2, Borrelia; relapsing fever Associating Factor 1, gene map locus bp base pair 11q23.1; encodes a B-cell specific coact- 2,3-BPG 2,3-biphosphoglycerate, also ivator of octamer-binding transcription known as 2,3-DPG factors, Oct1 and Oct2; the gene con- B prolymphocytic leukaemia a tributes to the BOB1-BCL6 fusion gene leukaemia of relatively large mature in B-lineage non-Hodgkin’s lymphoma B-lineage cells with plentiful cytoplasm associated with t(3;11)(q27;q23); BOB1 is and a large prominent nucleolus (Fig. 14) expressed in the neoplastic cells of nodu- BRCA1 a gene, Breast Cancer, type 1, lar lymphocyte predominant Hodgkin’s gene map locus 17q21; encodes a widely disease but not those of classical Hodgkin’s expressed nuclear phosphoprotein which disease may be involved in DNA repair; implic- BOB-1 a co-activator of the transcription ated in familial breast and breast plus factors, Oct1 and Oct2 ovarian cancer Bombay blood group the hh O blood BRCA2 a gene, Breast Cancer 2, early- group in which there is inability to onset, gene map locus 13q12.3; encodes express A and B antigens as a result of a a DNA repair protein that functions in lack of the precursor H substance which, conjunction with the RAD51 recombi- in turn, results from the lack of a specific nase; implicated in familial breast and glycosyltransferase that is encoded by the breast plus ovarian cancer H allele at the FUT1 locus (see Fig. 3, p. 4) breakpoint the point in a gene or on a bone marrow the tissue present in the chromosome where a breakage occurs, cavity of bones that has the potential to leading to rearrangement of a gene or a produce blood cells; yellow marrow is chromosome predominantly fat whereas red marrow bromodomain an evolutionarily con- has a high percentage of haemopoietic served motif found in proteins associated cells with chromatin and in nearly all nuclear HAE-B 01/13/2005 05:09PM Page 30

30 bronchi

Figure 13 Production and maturation of the B lymphocyte. Precursor B lymphoblasts are produced in the bone marrow from the common lymphoid progenitor. They rearrange ﬁrst an immunoglobulin heavy chain gene and then one or more light chain genes. The naïve B cell passes into the blood stream and thus to a primary follicle of the lymph node. If the naïve B cell recognizes antigen presented by a specialized antigen-presenting cell, further development occurs, to either an immunoblast, giving rise to a medullary plasmacytoid lymphocyte, or to a B blast, which remains in the follicle. The follicle also contains follicular dendritic cells which, by means of their Fc and complement receptors, can trap antigen in the form of immune complexes. If the B blast is presented with antigen by a follicular dendritic cell and is aided by helper T cells, it becomes a centroblast and undergoes somatic hypermutation, afﬁnity maturation and isotype switching; by this stage the primary follicle has become a secondary follicle. The centroblast becomes a centrocyte and, on leaving the follicle, the mature B cell ultimately becomes either a memory B cell or an antibody-secreting plasma cell in bone marrow or other tissues.

Bone marrow Precursor B lymphoblasts Peripheral blood Lymph node Naive B cell Primary Primary follicle follicle developing into Germ line secondary immunoglobulin follicle genes

Rearranged Rearranged Antigen- light chain IGH genes Naive presenting genes B cell cell Lymph node Secondary follicle Immunoblast Centroblast Paracortex B blast

Follicular Helper T cell Plasmacytoid dendritic cell lymphocyte Helper Centrocyte T cell Medulla Memory B cell Monocytoid Marginal B cell zone Bone Peripheral marrow blood and other tissues Memory B cell Plasma cell

histone; bromodomains have been shown bronchoconstriction reversible narrow- to bind to acetylated histones ing of the airways bronchi intermediate sized air passages brucellosis disease resulting from bronchioles small air passages infection by organisms of the genus bronchitis acute or chronic inﬂamma- Brucella tion of the bronchi BSH British Society for Haematology HAE-B 01/13/2005 05:09PM Page 31

busulphan 31

Figure 14 A prolymphocyte. in this gene lead to X-linked agamma- Transmission electron micrograph of a globulinaemia, characterized by a failure prolymphocyte in B-lineage prolymphocytic of B-cell development and agammaglob- leukaemia. The very large nucleolus and abundant ulinaemia, but with normal T and NK cells cytoplasmic mitochondria are apparent. BTL see CHIC2 buffer a substance that tends to control the hydrogen ion concentration in a solution so that pH change on adding an acid or an alkali is lessened buffy coat the beige-coloured layer of white cells that appears above the red cells when blood is centrifuged or allowed to sediment Burkitt’s lymphoma a highly aggressive B-cell lymphoma with distinctive cytological, histological, cytogenetic and molecular genetic features burr cell an unsatisfactory term which is sometimes used to describe a variety of types of spiculated cell burst forming unit-erythroid (BFU-E) an erythroid progenitor which gives rise BTK a gene, Bruton agammaglobuli- to a number of erythroid colonies (CFU- naemia Tyrosine Kinase, also known as E) (see Fig. 41, p. 122) B-cell Progenitor Kinase, BPK, gene map busulphan an alkylating agent occa- locus Xq21.3-q22, encodes a nonrecep- sionally used in the treatment of chronic tor tyrosine kinase that is essential for myeloid leukaemias and other myelopro- B-cell development; germline mutations liferative disorders HAE-C 01/13/2005 05:10PM Page 32

c (i) a cytogenetic abbreviation indicating susceptibility to pyogenic infections, mem- a constitutional abnormality (ii) expres- branoproliferative glomerulonephritis and sed in the cytoplasm (iii) an indication rash that a gene is a human cellular gene, C4 a component of the classical and homologous to a viral gene, e.g. c-ABL mannose-binding lectin complement cf. v-abl pathways (see complement system) C one of the complement components C4 deficiency an inherited deficiency or an abbreviation for the pyrimidine, of C4, when homozygous associated cytosine with increased probability of developing C1 also known as C1 esterase, the first systemic lupus erythematosus component of the complement pathway, C4A, C4B genes at 6p21.3 encoding composed of one molecule of C1q, two complement component 4, which carries molecules of C1s and two molecules of antigens of the Chido/Rodgers blood C1r (see complement system) group system C1 esterase inhibitor C1 inhibitor, the C4ST a gene, Chondroiton 4-O-Sulpho- inhibitor of the activated form of the first transferase 1, gene map locus 12q23, component of complement which is rearranged and dysregulated in C1 esterase inhibitor deficiency an t(12;14)(q23;q32) in chronic lymphocytic inherited or acquired deficiency of C1 leukaemia esterase inhibitor C5, C6, C7, C8 and C9 components of C1 inhibitor see C1 esterase inhibitor the classical, alternative and mannose- C1q deficiency an inherited deficiency binding lectin complement pathways (see of C1q, when homozygous associated complement system) with high probability of developing sys- Cabot’s rings thread-like rings or loops temic lupus erythematosus within red cells, mainly described on films C1r and C1s deficiency an inherited stained with a Wright’s stain and very deficiency of C1r and C1s, when homozy- uncommon in May–Grünwald–Giemsa gous associated with high probability of stained films developing systemic lupus erythematosus cachectic suffering from cachexia C2 a component of the classical and cachexia marked wasting, e.g. due to mannose-binding lectin complement path- severe malnutrition or malignant disease ways (see complement system) cadherin a member of the family of C2 deficiency an inherited deficiency of calcium-dependent cell adhesion mole- C2, when homozygous associated with cules which mediate homotypic cell-cell high probability of developing systemic adhesion; they include N-cadherin lupus erythematosus (neuronal cadherin), P-cadherin (placen- C3 a component of the classical, alternat- tal cadherin) and E-cadherin (epithelial ive and mannose-binding lectin comple- cadherin); ‘classical’ cadherins have a ment pathways (see complement system) highly conserved cytoplasmic domain C3 deficiency an inherited deficiency of that associates with intra-cellular C3, when homozygous associated with actin microfilaments via catenins; ‘non-

32 HAE-C 01/13/2005 05:10PM Page 33

CASP10 33

classical’ cadherins are more diverse and Candida a genus of fungi capable of have cytoplasmic domains that connect causing superficial or deep infections, to intermediate filaments, e.g. desmin (see the latter particularly in patients with also protocadherin) immune deficiency or other illnesses caisson disease decompression illness candidiasis disease resulting from infec- occurring in deep-sea divers, consequent tion by micro-organisms of the genus on too rapid decompression leading bub- Candida bles of nitrogen to appear in the blood CAPD continuous ambulatory peritoneal stream, can cause bone marrow necrosis dialysis Calabar swellings subcutaneous swel- capillary (i) a small thin walled blood ling of the shins as a consequence of vessel connecting arterioles to venules loiasis (ii) a very fine tube CALM a gene, Clathrin Assembly carbonic anhydrase an erythrocyte Lymphoid Myeloid leukaemia, gene enzyme which catalyses the conversion of

map locus 11q14, also known as CO2 and H2O into carbonic acid, H2CO3; Phosphatidylinositol-binding Clathrin the most abundant protein in an erythro- Assembly Lymphoid Myeloid leukaemia cyte after haemoglobin, being present in protein—PICALM and Assembly sufficient quantities to produce a visible Protein, 180 kD—AP180; encodes a band if a protein stain is used for staining phosphoinositide-binding protein which haemoglobin electrophoresis membranes promotes the assembly of and restricts carboxyhaemoglobin haemoglobin the size of clathrin-coated vesicles; CALM that has been chemically altered by com- contributes to bination with carbon monoxide •a MLL-CALM fusion gene in acute carcinocythaemia circulation of carci- myeloid leukaemia associated with noma cells in the peripheral blood inv(11)(q14.2q23.1) carcinogen a substance capable of giv- •a CALM-AF10 fusion gene in acute ing rise to cancer myeloid leukaemia carcinogenesis the process by which CAN Cain gene, also known as an external influence or substance, e.g. a NUP214—Nucleoporin, 214 kD; gene chemical or a radioactive isotope, gives map locus 9q34.1; CAN is so named rise to cancer because of its proximity to the ABL gene carcinogenic able to cause cancer at 9q34 (Cain and Abel, the sons of carcinoid tumour a neuroendocrine Adam) also indicating Cancer gene tumour that secretes serotonin intron on Nine; encodes a protein which CARD domain Caspase Recruitment forms part of the nuclear pore complex; Domain; a homotypic interaction motif CAN contributes to present in proteins that regulate apopto- • the DEK-CAN (DEK-NUP214) fusion sis e.g. BCL10, caspase 2, ApaF1 gene in t(6;9)(p23;q34) associated with carrier a person who has one copy of acute myeloid leukaemia in which the a mutant gene that causes a significant fusion protein localizes to the nucleus and phenotypic abnormality in homozygotes, may function as a transcription factor a heterozygote for a mutant gene • the SET-CAN (SET-NUP214) fusion cascade a sequence of reactions, e.g. the gene, formed by fusion of two genes coagulation cascade at 9q34, associated with acute myeloid caseating granuloma a granuloma leukaemia with central caseation necrosis, typical cancellous bone trabecular bone, bone of tuberculosis but not pathognomonic composed of anastomosing spicules caseation a form of tissue necrosis cancer a general term usually used to when a crumbly cheese-like material is indicate any malignant neoplasm produced cancer suppressor gene see tumour CASP10 a caspase gene, gene map locus suppressor gene 2q23-q34, mutations of which underlie HAE-C 01/13/2005 05:10PM Page 34

34 caspase

type II autoimmune lymphoproliferative lead to elevated cAMP levels; in addition syndrome, also known as FLICE, FAD- CBP has inherent acetylase activity; CBP Like Ice coactivates several tissue-specific tran- caspase a family of cysteine proteases scription factors including the haemo- that mediate apoptosis poietic transcription factors, AML1 and Castleman’s disease an inflammatory GATA1, and the muscle-specific tran- condition of lymph nodes, also known as scription factor, MyoD; mutations in angiofollicular lymph node hyperplasia CBP result in the Rubinstein–Taybi syn- and giant lymph node hyperplasia; drome (RTS), characterized by mental human herpesvirus 8 (HHV8) infection retardation, skeletal abnormalities, and is one aetiological factor an increased propensity for neoplasms, CAT scan computerized axial tomogra- including leukaemia; part of CBP fuses phy scan with: catabolism the breakdown or degrada- • part of the MOZ gene to form MOZ- tion of large energy-rich molecules within CBP in M5 acute myeloid leukaemia cells (see also metabolism) associated with t(8;16)(p11;p13) catalyse to increase the rate of a chem- • part of the MLL gene to form MLL- ical reaction CBP in M2 acute myeloid leukaemia and cathepsin G a protease which is one of therapy-associated myelodysplastic syn- the constituents of azurophilic granules drome associated with t(11;16)(q23;p13) of neutrophils • part of the MORF gene at 10q22 to cation positively charged ion form both MORF-CBP and CBP-MORF cat scratch disease a disease resulting genes in M5 acute myeloid leukaemia from infection by micro-organisms of the associated with t(10;16)(q22;p13) genus Afipia or the genus Rochalimaea, CCAAT/Enhancer-Binding Protein ε transmitted by the bite or scratch of a cat a basic leucine zipper motif, myeloid- and causing fever and lymphadenopathy specific transcription factor encoded by CBC complete blood count C/EBPε CBFB a gene, Core Binding Factor Beta, CCNA1 the gene encoding cyclin A1, gene map locus 16q22; encodes a tran- gene map locus 13q12.3-q13, normally scription factor that does not bind DNA expressed in testes and brain, it is over- directly but interacts with one of three expressed in about a quarter of patients runt domain containing proteins encoded with acute myeloid leukaemia by either RUNX1 (AML1), RUNX2 CCNA2 the gene encoding cyclin A2, (AML3) or RUNX3 (AML2) to form one gene map locus 4q27, a widely expressed of three possible heterodimeric active cyclin which promotes both G1/S and transcription factors; each transcription G2/M transitions (see cell cycle); factor has a distinct normal pattern of repressed by PLZF; it is overexpressed expression and function (see also AML1 in breast cancer and Fig. 29, p. 107); CBFB contributes to CCNB1 the gene encoding cyclin B1, gene the fusion gene CBFB-MYH11 in M4Eo map locus 5q12, widely expressed, pre- acute myeloid leukaemia associated with dominantly in the G2/M phase of the cell inv(16)(p13q22) and t(16;16)(p13;q22); cycle when it is phosphorylated and the fusion gene probably has a dominant translocated into the nucleus; with CDK1 negative effect on AML1 function and cyclin F, is a component of M-phase CBP CREB (Cyclic adenosine mono- promoting factor; degraded by ubiquitin- phosphate Responsive Element Binding mediated proteolysis at the end of meta- protein) binding protein, CREBBP; gene phase; it is overexpressed in malignant map locus 16p13; encodes a widely and some benign breast disorders, and in expressed bromodomain protein which squamous metaplasia of the oesophagus binds to and coactivates CREB—a tran- CCNC the gene encoding cyclin C, gene scription factor activated by signals that map locus 6q21; along with CDK8, cyclin HAE-C 01/13/2005 05:10PM Page 35

CD2 35

C forms an inhibitory component of the prostate, reaches its highest levels of RNA polymerase II holoenzyme com- expression in late G2 phase of the cell plex; it is hemizygously deleted in some cycle cases of acute lymphoblastic leukaemia CCNH the gene encoding cyclin H, gene CCND1 see BCL1 map locus 5q13.3-q14; encodes a protein CCND2 the gene encoding cyclin D2, gene which, along with CDK7 comprises Cdk- map locus 12p13, normally expressed Activating Kinase (CAK) during the G1 phase of the cell cycle; CCNT1 the gene encoding cyclin T1, gene brought into proximity to the λ gene map locus chromosome 12, see CDK9 enhancer in t(12;22)(p13;q11) associated CD cluster of differentiation, a system with a case of Richter’s transformation; for classifying monoclonal antibodies there was also loss of a negative regula- according to their antigenic speciﬁcity; tory element; it is overexpressed in col- antibodies within the same cluster recog- orectal cancer, gastric cancer (indicates nize the same antigen, as determined by poor prognosis) and male germ cell immunoprecipitation, binding inhibition tumours experiments or both; antibodies of the CCND3 the gene encoding cyclin D3, same CD category have similar, but not gene map locus 6p21.1, normally ex- necessarily identical, patterns of tissue pressed late in the G1 phase of the cell reactivity cycle; it is: CD1 a cell surface glycoprotein, a family • dysregulated by proximity to the IGH of transmembrane proteins (CD1a, locus in 2–4% of patients with multi- CD1b, CD1c, CD1d and CD1e) non- ple myeloma and in some patients with covalently linked with β2 microglobulin; splenic lymphoma with villous lympho- CD1a, CD1b and CD1c function in cytes and transformed marginal zone T-cell responses to glycolipid antigens; lymphoma associated with t(6;14)(p21;q32) expressed on cortical thymocytes (CD1a • dysregulated by proximity to the λ strongly, CD1b moderately and CD1c gene in one patient with multiple weakly) and thought to have a role in myeloma associated with t(6;22)(p21;q11) thymic T-cell development; expressed on CCNE the gene encoding cyclin E, gene about a third of normal B cells (CD1b map locus 19q13.1, overexpressed in sev- and c), mature and some immature den- eral types of cancer including bladder and dritic cells, interdigitating reticulum cells gastric cancer, overexpressed in chronic (CD1b and c), Langerhans cells and lymphocytic leukaemia intestinal epithelium (CD1d only); not CCNF the gene encoding cyclin F, also expressed on mature T cells; has a role in known as F-Box only protein 1, FBX1; antigen presentation. CD1a is expressed gene map locus 16p13.3, encodes a pro- on Langerhans cells, but not on interdigit- tein containing a novel domain, the F- ating dendritic cells, follicular dendritic box which is present in proteins involved cells or macrophages in ubiquitin-mediated proteolysis; a com- CD1 is expressed on blast cells of some ponent of M-phase promoting factor T-lineage acute lymphoblastic leukaemia, CCNG1 the gene encoding cyclin G, gene the cells of some B-cell neoplasms and map locus 5q32-q34, encodes a protein the cells of Langerhans cell histiocyto- induced by DNA-damaging agents via sis; it is less often expressed in chronic a p53-dependent mechanism; normally lymphocytic leukaemia than on normal B expressed in lymphocytes, skeletal muscle, cells, although in other B-cell neoplasms ovary and kidney; unusual amongst expression is often increased cyclins in that its mRNA level does not CD2 receptor for sheep red blood cells, vary during the cell cycle (previous designations LFA-2 and leuco- CCNG2 the gene encoding cyclin G2, a cyte function-associated antigen 1), binds protein closely related to cyclin A, nor- to CD58 on antigen presenting cells and is mally expressed in spleen, thymus and costimulatory for B cells, expressed on HAE-C 01/13/2005 05:10PM Page 36

36 CD3

cortical and late thymocytes, mature T body (keliximab) has been used in cells, most NK cells; expression in T cells therapy of severe asthma and anti-CD4 increases with repeated antigen stimula- monoclonal antibodies have also been tion; expressed on cells of systemic mas- used in psoriasis tocytosis but not on normal mast cells; a CD4 is expressed on blast cells of recombinant protein bearing the CD2- many cases of T-lineage acute lympho- binding moiety of CD58 (alefacept) has blastic leukaemia and on cells of many been used to target memory T cells in the leukaemias/lymphomas of mature T cells; therapy of psoriasis sometimes expressed on blast cells in CD2 is expressed on blast cells of many acute myeloid leukaemia, particularly in cases of T-lineage acute lymphoblastic M4 and M5 acute myeloid leukaemia; leukaemia and cells of many leukaemias/ expressed in Langerhans cell histiocytosis lymphomas of mature T cells; may be CD5 a cell surface glycoprotein, a signal expressed on the leukaemic cells in M3 transducing molecule that modulates sig- and M4Eo acute myeloid leukaemia nalling through the T- and B-cell receptor CD3 a complex of at least ﬁve membrane- complexes: ligand of the B-cell antigen bound polypeptides (CD3γ, CD3δ, CD72; expressed on cortical and late thy- CD3ε, CD3zeta and CD3eta) that are mocytes and some early thymocytes, on non-covalently associated with each other mature T cells, on a subset of normal B and with the T-cell receptor; expressed on cells (found in the mantle zone of germi- late thymocytes and mature T cells, the nal centres and in small numbers in the complex is essential for antigen recogni- blood); CD5+ lymphocytes are expanded tion and binding by T cells and subse- in various autoimmune diseases, e.g. quent signal transduction; monoclonal rheumatoid arthritis and high circulating antibodies to CD3 (muromonab) have levels of soluble CD5 are seen in Sjogren’s been used for the treatment of renal Syndrome; ricin-conjugated-CD5 mono- and cardiac allograft rejection and acute clonal antibodies (XomaZyme-CD5 graft-versus-host disease; a bi-speciﬁc Plus) have been used for the treatment of CD3, CD19 antibody has therapeutic acute graft-versus-host disease potential in non-Hodgkin’s lymphoma CD5 is expressed on blast cells of many CD3 is expressed on blast cells of many cases of T-lineage acute lymphoblastic cases of T-lineage acute lymphoblastic leukaemia, and cells of many T-lineage leukaemia and neoplastic cells of many leukaemias/lymphomas and on cells of leukaemias/ lymphomas of mature T cells chronic lymphocytic leukaemia and man- CD4 a cell surface glycoprotein, co- tle cell lymphoma; expression of CD5 in receptor for MHC class-II restricted diffuse large B-cell lymphoma is associ- antigen-induced T-cell activation (see ated with adverse prognostic features and Fig. 42, p. 123); co-expressed with CD8 worse survival on cortical thymocytes and expressed on CD6 an adhesion molecule mediating a major subset of late thymocytes and binding of developing thymocytes to mature T cells (helper/inducer) without thymic epithelium, expressed on thymo- co-expression of CD8; expressed on cytes at all stages of development but may immature myeloid cells, eosinophils, be weakly expressed on the most imma- monocytes, macrophages and Langer- ture cells; expressed on the majority of hans cells but not interdigitating den- peripheral blood T cells and a subset of dritic cells or follicular dendritic cells, normal B cells (involved in the produc- receptor for human herpesvirus 7; recep- tion of autoreactive antibodies); CD6+ T tor for HIV, binding to the envelope cells are thought to be involved in graft- protein gp120; the number of CD4+ versus-host disease; expressed at low levels lymphocytes is greatly reduced in adv- on a subset of CD34+ haemopoietic stem anced HIV infection and overt AIDS; cells and may mediate their attachment to a chimaeric anti-CD4 monoclonal anti- stromal cells by binding to CD166 HAE-C 01/13/2005 05:10PM Page 37

CD10 37

CD6 is expressed on the cells of chronic CD9 MRP-1, a cell surface glycoprotein, lymphocytic leukaemia; it is expressed a member of the transmembrane 4 fairly consistently on the blast cells of T- or tetraspanin superfamily of proteins, lineage acute lymphoblastic leukaemia expressed on haemopoietic stem cells, CD7 a cell surface glycoprotein, a mem- megakaryocyte progenitors, platelets, ber of the immunoglobulin superfamily early B cells, activated B and T cells, of cell surface glycoproteins, expressed eosinophils, basophils, normal and neo- on thymocytes, the majority of mature T plastic mast cells, endothelial cells, neural cells and NK cells; expressed on some and glial cells of the brain and peripheral common lymphoid progenitor cells; ex- nerves, vascular and cardiac smooth pressed a subset of immature myeloid cells; muscle and epithelial cells; expressed on ricin-conjugated monoclonal antibodies bone marrow stromal cells; in platelets to CD7 have been used for the treatment is associated with CD36; expression in of T-cell leukaemias and lymphomas and, melanoma and breast cancer may be together with anti-CD3, for the treatment indicative of a better prognosis; however, of acute graft-versus-host disease has a role in transendothelial migration CD7 is expressed on blast cells of T- of melanoma cells lineage acute lymphoblastic leukaemia, CD9 is expressed by B-lineage leukaemic cells of T-lineage prolympho- acute lymphoblastic leukaemia cells, the cytic leukaemia and, less often, the cells of leukaemic cells of hypergranular pro- other T-lineage leukaemias/lymphomas; it myelocytic leukaemia and less often the is expressed on blast cells of a significant leukaemic cells in other types of acute minority (c. 15%) of cases of acute myeloid myeloid leukaemia leukaemia—this expression may be useful CD10 a cell surface glycoprotein, neutral in monitoring minimal residual disease endopeptidase or neprilysin, a cell surface CD8 a heterodimeric glycoprotein, metalloproteinase, the common ALL having an α and a β chain encoded by antigen, expressed on a subset of normal closely linked genes on chromosome 2; a B-cell progenitors including B cells in ger- co-receptor for MHC class I molecules; minal centres and ‘haematogones’—non- the α chain gene also gives rise to an alter- neoplastic immature B-lineage lymphoid natively spliced transcript that encodes cells that are seen particularly in the bone a small secreted polypeptide which is marrow of children; expressed on a thought to have an immunoregulatory minority (less than 10%) of circulating B role; expressed on cortical thymocytes cell in neonates, on neutrophils, on bone together with CD4; expressed on a subset marrow stromal cells, on renal, bronchial of late thymocytes and mature T cells and intestinal epithelium and on breast without co-expression of CD4, these myoepithelium; expressed on a significant being cytotoxic/suppressor T cells that proportion of many non-haemopoietic recognize antigen in the context of class I tumours including: renal cell, transitional major histocompatibility antigens; expres- cell and prostatic carcinoma, pancreatic sed on macrophages but not osteoclasts; and hepatocellular carcinoma, melanoma expressed on NK cells and various sarcomas CD8 is expressed on cells of most cases CD10 is expressed on blast cells of the of large granular lymphocyte leukaemia majority of cases of B-lineage acute and on cells of a smaller proportion of lymphoblastic leukaemia, more weakly on cases of other T-lineage leukaemias/ the blast cells of some cases of T-lineage lymphomas acute lymphoblastic leukaemia, on the CD8 lymphopenia a congenital immune cells of many cases of follicle centre cell deficiency syndrome resulting from lymphoma and a lower proportion of mutation in the ZAP-70 gene, gene map cases of other B-lineage non-Hodgkin’s locus 2q12, which encodes a tyrosine lymphomas; expressed on some myeloma kinase important in T-cell signalling cells HAE-C 01/13/2005 05:10PM Page 38

38 CD11a

CD11a a cell surface glycoprotein, mature thymic dendritic cells; CD11b/ LFA1α (α chain of leucocyte function CD18 promotes binding and phagocyto- α associated antigen 1) or L integrin, sis of complement coated particles and shares a beta subunit (CD18) with has a role in interactions of neutrophils other members of a family of leukocyte and monocytes with stimulated endothe- surface membrane antigens; CD11a is lium; expression is absent in leucocyte expressed as a heterodimer with CD18; adhesion deficiency type I, a congenital CD11a/CD18 is an adhesion molecule disorder characterized by neutrophilia β α β of the 2 integrin family ( L 2 integrin) and recurrent bacterial infections due to which is expressed on all leucocytes and deficiency of the beta-2 integrin subunit is important in many inflammatory and (CD18) of the leukocyte cell adhesion immune responses; expressed on macromolecule; administration of G-CSF phages but not osteoclasts; CD11a/CD18 increases expression of CD11b/CD18 is necessary for lymphocyte recirculation on neutrophils; on monocytes CD11b through lymph nodes; CD11a/CD18 is expressed more strongly than CD15 binds to ICAM-1 (CD54), ICAM-2 whereas on neutrophils the reverse is true; (CD102) and ICAM-3 (CD50); expres- used by Mycobacterium tuberculosis, the sion is absent in leucocyte adhesion human immunodeficiency virus and deficiency type I, a congenital disorder flaviviruses, such as the West Nile virus, characterized by neutrophilia and recur- to enter cells rent bacterial infections due to deficiency CD11b is expressed on hairy cells; of the beta-2 integrin subunit (CD18) of expressed on cells of many cases of acute the leukocyte cell adhesion molecule; anti- myeloid leukaemia, particularly those CD11a antibodies have been used experi- with monocytic differentiation; occasion- mentally in the treatment of psoriasis ally expressed on chronic lymphocytic CD11a is expressed (with CD18) in leukaemia cells α some cases of multiple myeloma; CD11a/ CD11c a cell surface glycoprotein, X CD18 may be expressed in follicular lym- integrin chain, also known as p150 (p150, phoma and strong expression is indicat- 95); it shares a beta subunit (CD18) with ive of a better prognosis; not expressed other members of a family of leukocyte on chronic lymphocytic leukaemia cells; surface membrane antigens; it is expression in acute myeloid leukaemia expressed as a heterodimer with CD18 α β correlates with a worse prognosis (CD11c/CD18 or X 2 integrin); ex- α CD11b a cell surface glycoprotein, M pressed on monocytes, macrophages, NK integrin chain, also known as mac1 or cells and neutrophils (more weakly than MO1, it shares a beta subunit (CD18) on monocytes); not expressed on osteo- with other members of a family of leuko- clasts; expressed on normal and neoplas- cyte surface membrane antigens; CD11b/ tic mast cells but not basophils; expressed α β CD18 is M 2; it is a C3bi receptor (CR3 on some but not all dendritic cells— complement receptor); also binds to specifically, on peripheral blood dendritic CD54 and extracellular matrix proteins; cells of myeloid origin but not on those of expressed on mature monocytes and lymphoid origin; expressed on some but macrophages but not osteoclasts; expres- not all mature lymph node dendritic cells; sed on NK cells; expressed more weakly expressed, together with CD11b, on a on mature neutrophils but expression is subset of mature thymic dendritic cells; increased when neutrophils are activated; expressed on activated T and B cells; sometimes expressed on basophils and CD11c is a ligand for iC3b and fibrino- variably expressed on mast cells; expres- gen; expression is absent in leucocyte sed on a subset of B cells (CD5+ activated adhesion deficiency type I, a congenital B cells) and a subset of T cells (cytotoxic disorder characterized by neutrophilia CD8+ T cells); expressed, together with and recurrent bacterial infections due to high levels of CD11c, on a subset of deficiency of the beta-2 integrin subunit HAE-C 01/13/2005 05:10PM Page 39

CD15 39

(CD18) of the leukocyte cell adhesion necrosis factor and upregulation of cellu- molecule lar adhesion molecules; soluble CD14 CD11c is expressed on hairy cells and is required for endotoxin signalling to cells of some cases of hairy cell variant endothelial and epithelial cells leukaemia and splenic lymphoma with CD14 is expressed on the blast cells of villous lymphocytes and occasionally on many cases of acute myeloid leukaemia, chronic lymphocytic leukaemia and small particularly those showing monocytic lymphocytic lymphoma cells but not usu- differentiation—it is a fairly speciﬁc but ally on cells of other lymphoproliferative not very sensitive marker of M4 and disorders M5 acute myeloid leukaemia; aberrant CDw12 the gene encoding this antigenic expression of CD14 in chronic lympho- determinant has not yet been cloned; cytic leukaemia has been associated expressed on monocytes, neutrophils, with a worse prognosis; expressed in natural killer cells and platelets the majority of cases of Langerhans cell CD13 a membrane-bound zinc-binding histiocytosis metalloproteinase, also known as amino- CD15 a fucose-containing, cell surface peptidase N; expressed as a homodimer, glycoprotein, also known as alpha-3 that degrades regulatory peptides and fucosyltransferase, which is the ligand of may modify peptides bound to MHC E and P selectins (CD62E and CD62P); class II molecules; expressed on early expressed on maturing cells of monocyte committed progenitors of granulocytes lineage and more weakly on maturing and monocytes and on maturing cells cells of neutrophil and eosinophil lineages, of these lineages; expressed on dendritic from the promyelocyte stage onwards; cells; expressed on macrophages and not expressed on basophils or mast cells; osteoclasts; expressed on mast cells and CD15s is the sialylated form; monoclonal their precursors; expressed on endothelial antibodies detect either the sialylated cells when there is angiogenesis but not form, CD15s (e.g. McAb FH6 or CSLEX1) expressed on normal endothelial cells; or non-sialylated form of CD15 (LeuM1 expressed on bone marrow stromal cells, and 80H5); the sialylated form is the osteoclasts, bile duct canalicular cells, ligand for CD62E; Rambam–Hasharon proximal tubule cells of the kidney and syndrome is an autosomal recessive inborn the intestinal brush border (where CD13 error of fucose metabolism associated is thought to function as a coronavirus with neutrophilia and recurrent infec- receptor) tions; the immune defect, designated leu- CD13 is expressed on the blast cells of cocyte adhesion deﬁciency type II, results the majority of cases of acute myeloid from lack of sialylated CD15 (CD15s) leukaemia, being more often negative in which is a ligand for selectins—as a M6 and M7 acute myeloid leukaemia; result, neutrophils which fail to express expressed on some myeloma cells CD15s cannot bind normally to endothe- CD14 a glycosylphosphatidylinositol (GPI)- lial E and P selectins and cannot migrate anchored cell surface glycoprotein, normally into tissues; in addition, the receptor for endotoxin (lipopolysaccha- patient’s red blood cells lack H substance, ride–lipopolysaccharide binding protein a fucosylated glycoprotein, which is the complex); expressed on monocytes and precursor molecule of the A, B and O macrophages and more weakly on neu- blood groups and consequently patients trophils; not expressed on basophils or manifest the Bombay blood type mast cells; expressed on circulating CD15 is expressed on the blast cells dendritic cells and some immature tissue of many cases of acute myeloid leuk- dendritic cells; expressed on macrophages aemia particularly those with monocytic but not osteoclasts; when endotoxin differentiation; it is expressed on Reed– is bound to CD14 of neutrophils and Sternberg cells and mononuclear Hodgkin’s monocytes there is release of tumour cells (except in nodular lymphocyte HAE-C 01/13/2005 05:10PM Page 40

40 CD15u

predominant Hodgkin’s disease), a worse tions; CD18 binds unopsonized bacteria prognosis in Hodgkin’s disease hav- and fungi, thus promoting phagocytosis; ing been related to expression of non- CD18 is expressed on all leucocytes; a sialylated rather than sialylated CD15; proteolytically truncated form of CD18 is expressed on cells of a small proportion a marker of activation of neutrophils and of cases of non-Hodgkin’s lymphoma monocytes; β2 integrins are expressed CD15u sulphated CD15 on activated eosinophils, permitting their CD16 a glycosylphosphatidylinositol (GPI)- adhesion to ICAM-1 on endothelial anchored integral membrane protein, cells; expressed on basophils; variably part of the low affinity Fcγ receptor, expressed on mast cells; not expressed on FcRIII which mediates phagocytosis and normal plasma cells; administration of antibody-dependent cytotoxicity; expres- G-CSF increases expression of CD11b/ sed on NK cells (mature NK cells but not CD18 on neutrophils NK precursors or immature NK cells), CD18 may be expressed on myeloma some T cells, neutrophils and macro- cells; CD11a/CD18 may be expressed in phages but not eosinophils or osteoclasts; follicular lymphoma and strong expres- not expressed on basophils or mast cells sion is indicative of a better prognosis; constitutive expression in neutrophils is not expressed on chronic lymphocytic cytoplasmic with transient surface mem- leukaemia cells brane expression occurring when they are CD19 a cell surface glycoprotein, a signal exposed to complement; includes CD16a transduction molecule, regulating B-cell and CD16b, which differ somewhat in development, activation and prolifera- structure but are expressed on the same tion; part of a large signal transduction range of cells complex that also involves CD21 and Polymorphisms in FcγRIIIa correlate CD81, expressed on B lymphocytes and with responsiveness to rituximab (anti- their precursors; it is one of the earliest CD20) therapy of the B-lineage restricted antigens to be CD16 is expressed on the cells of a expressed; expressed on follicular den- significant minority of cases of acute dritic cells; may be expressed on normal myeloid leukaemia—a fairly specific but plasma cells and their precursors not very sensitive marker of M4 and CD19 is expressed on the cells of the M5 acute myeloid leukaemia; expressed majority of cases of B-lineage acute lym- by some NK-cell neoplasms, specifically phoblastic leukaemia and leukaemia/ aggressive NK cell leukaemia/lymphoma lymphoma of B-lineage; not usually and some cases of nasal-type NK-cell expressed on myeloma cells; an anti- leukaemia lymphoma but not blastic CD19 immunotoxin conjugated to the NK-cell lymphoma tyrosine kinase inhibitor, Genistein, has CDw17 an antigenic determinant defined been employed in therapy of acute lym- by the lactosyl disaccharide group of the phoblastic leukaemia and B-lineage non- glycosphingolipid lactosyl ceramide; the Hodgkin’s lymphoma; a bi-specific CD3, protein carrying this antigenic determin- CD19 antibody has therapeutic potential ant is not known; expressed on mono- in non-Hodgkin’s lymphoma cytes, neutrophils, basophils (but not CD20 a cell surface glycoprotein, ex- mast cells), platelets, a subset of B cells pressed on B lymphocytes and their pre- and tonsillar dendritic cells cursors but not the earliest identifiable CD18 an integral membrane protein, the precursors; weakly expressed on a T-cell β β chain of the 2 integrins CD11a/CD18, subset; expressed on follicular dendritic CD11b/CD18 and CD11c/CD18; muta- cells; humanized murine monoclonal anti- tions in the CD18 gene are responsible for bodies to CD20, rituximab (Mabthera, leucocyte adhesion deficiency type I, a Rituxan), have been used in severe congenital disorder characterized by neu- autoimmune disease including pure red trophilia and recurrent bacterial infec- cell aplasia, autoimmune haemolytic HAE-C 01/13/2005 05:10PM Page 41

CD23 41

anaemia, immune thrombocytopenia in clonal antibodies, have been found useful the context of graft-versus-host disease in controlling post-transplant lympho- and polyneuropathy caused by IgM anti- proliferative disorder bodies; anti-CD20 antibodies may also CD21 is expressed on cells of most be useful in Epstein–Barr virus related cases of chronic lymphocytic leukaemia post-transplant lymphoproliferative dis- and on cells of about 50% of cases of B- ease and in human herpesvirus 8-related lineage non-Hodgkin’s lymphoma but multicentric Castleman’s disease expression on chronic lymphocytic CD20 is expressed on blast cells of leukaemia cells is weaker than on normal some cases of B-lineage acute lym- B cells and does not support EBV trans- phoblastic leukaemia but not on the most formation; weakly expressed on hairy immature B lymphoblasts; expressed on cells; expressed on cells of some cases of cells of the majority of cases of B-lineage T-lineage acute lymphoblastic leukaemia; leukaemia/lymphoma but more weakly expressed by neoplastic cells of a minority expressed in chronic lymphocytic leuk- of cases of Hodgkin’s disease; when aemia than in other mature B-cell neo- linked to a radionucleide, monoclonal plasms; expressed in a minority of cases CD21 antibodies have been used in ther- of multiple myeloma but more often apy of B-cell neoplasms expressed in plasma cell leukaemia; CD22 Sialic acid-binding Immunoglobulin- expressed on neoplastic cells in nodular like Lectin 2, siglec-2, an adhesion and lymphocyte predominant Hodgkin’s dis- signalling cell surface glycoprotein, ease and expressed, more weakly on the which is a member of the sialoadhesion neoplastic cells of 30–40% of classical subclass of the Ig superfamily; CD22 Hodgkin’s disease; the murine mono- modulates the effect of antigen signalling clonal antibodies to CD20, including in B cells; expressed on B lymphocytes some linked to a radionucleide (e.g. and in the cytoplasm of their precursors; Yttrium-90 (90Y)-ibritumomab and variably expressed on mast cells; expres- Iodine-131(131I)-tositumomab), are used sion on basophils is detected with some in treatment of B-cell neoplasms, such but not all monoclonal antibodies as follicular lymphoma, chronic lympho- CD22 is expressed in the cytoplasm of cytic leukaemia and cold haemagglutinin the blast cells of most cases of B-lineage disease; the monoclonal antibody FMC7, acute lymphoblastic leukaemia but less widely used in diagnosis, appears to bind frequently on the surface membrane; ex- to a particular conformation of CD20, pressed on the surface membrane of cells probably a multimeric CD20 complex of most cases of B-lineage leukaemia/ CD21 a cell surface glycoprotein, forms lymphoma, including hairy cell leuk- part of a large signal transduction com- aemia but with the exception of the cells plex that also involves CD19 and CD81; a of chronic lymphocytic leukaemia in complement receptor, CR2 or C3dR, that which expression is weak or absent; binds C3d, C3dg and iC3b; complement anti-CD22 monoclonal antibodies, e.g. may activate B cells through CD21 bind- epratuzumab, including murine and ing with activated B cells no longer humanized antibodies linked to a expressing CD21; a receptor for EBV; radionucleide, have been used for the expressed on a subset of normal B cells treatment of B-lineage non-Hodgkin’s including follicular mantle zone and lymphoma; an anti-CD22 recombinant marginal zone lymphocytes; not expres- immunotoxin has been used in the treat- sed on B-cell precursors; expressed on ment of hairy cell leukaemia follicular dendritic cells, helping to distin- CD23 a cell surface glycoprotein, low guish them from interdigitating dendritic afﬁnity Fcε receptor (FcεRII); a negative cells, Langherhans cells and macro- feedback regulator of IgE synthesis; phages; CD21 monoclonal antibodies, expressed on B cells in the follicular used in conjunction with CD24 mono- mantle but not by proliferating germinal HAE-C 01/13/2005 05:10PM Page 42

42 CD24

centre B cells; expressed on 30–40% of CD25 a cell surface glycoprotein, the α peripheral blood B cells, on activated B chain of interleukin 2 receptor (IL2Rα); cells, a subset of T cells, eosinophils, high affinity IL2R is a complex of CD25 monocytes, macrophages, Langerhans with CD122 and CD132; expressed on cells, follicular dendritic cells, platelets activated B cells and T cells and on a and some stromal cells; mediates cyto- subset of regulatory T cells, on mono- kine release by monocytes; soluble CD23 cytes and on the cells of polyclonal B-cell is a B-cell growth factor; expressed less lymphocytosis; sometimes expressed on often on the cells of polyclonal B-cell lym- basophils but not expressed on normal phocytosis than on normal B cells; mast cells; a humanized anti-CD25 mon- expressed on epithelial cells, e.g. of stom- oclonal antibody, dacluzumab (Zenapax), ach. intestine and lung has been used for prevention of cardiac CD23 is expressed on cells of most allograft rejection and acute renal allo- cases of chronic lymphocytic leukaemia graft rejection; anti-CD25 antibodies and small lymphocytic lymphoma but in have been used experimentally in the only a minority of cases of prolympho- treatment of psoriasis; a first exon dele- cytic leukaemia and other categories of tion mutation in the CD25 gene has been non-Hodgkin’s lymphoma; expressed described, leading to a severe immun- more often in low grade lymphoma than odeficiency syndrome in high grade; soluble CD23 is of prog- CD25 is expressed on hairy cells, on the nostic significance in chronic lympho- cells of the great majority of cases of adult cytic leukaemia T-cell leukaemia/lymphoma and some- CD24 a heavily glycosylated glyco- times on other high grade lymphomas sylphosphatidylinositol (GPI)-anchored including anaplastic large cell lymphoma; cell surface glycoprotein, expressed on B expressed on mononuclear Hodgkin’s lymphocytes and their precursors, on cells and Reed–Sternberg cells; in non- activated T lymphocytes, on neutrophils, Hodgkin’s lymphoma, serum CD25 on eosinophils, on some epithelial cells correlates with tumour burden; may be and on carcinoma cells including cells of expressed on neoplastic mast cells, both small cell carcinoma of the lung; CD24 in systemic mastocytosis and acute mast has been reported to be a ligand for P- cell leukaemia; an immunotoxin directed selectin (CD62), a lectin expressed on at CD25 (LMB-2) has been used in ther- platelets and vascular endothelium; apy of hairy cell leukaemia, Hodgkin’s CD24/CD62 binding could represent a disease, cutaneous T-cell lymphoma and mechanism for tumour dissemination; adult T-cell leukaemia lymphoma CD24 monoclonal antibodies, used in CD26 a membrane bound serine exopep- conjunction with CD21 monoclonal tidase—dipeptidyl peptidase IV; adeno- antibodies, have been found to be useful sine deaminase binding protein; interacts in controlling post-transplant lympho- with CD45 and is a costimulatory proliferative disorder molecule for T-cell activation; cleaves CD24 is expressed on the blast cells of an essential cofactor for the entry of the majority of cases of B-lineage acute HIV into CD4+ Th1 T cells; up-regulated lymphoblastic leukaemia but not those on Th1 T cells by γ-interferon; cleaves associated with a cytogenetic rearrange- peptides from several chemokines, reduc- ment with an 11q23 breakpoint; expres- ing their ability to mediate chemotaxis sed on the cells of the majority of cases of without affecting their angiostatic poten- B-lineage leukaemia/lymphoma and on tial; expressed on mature thymocytes, blast cells of some cases of acute myeloid activated T cells, B cells, NK cells, leukaemia, particularly M4 and M5 acute macrophages, renal proximal tubule myeloid leukaemia for which it is a fairly cells, fibroblasts, some epithelial cells specific but not very sensitive marker; (including those of small intestinal weakly expressed on hairy cells epithelium, prostatic cells and biliary HAE-C 01/13/2005 05:10PM Page 43

CD31 43

canalicular cells), brain, heart, skeletal haemopoietic progenitor cells and is the muscle, endothelial cells and splenic sinus ligand of VCAM-1 on bone marrow lining cells; lack of expression of CD26 stromal endothelium, permitting trans- has been found useful in the identiﬁcation endothelial migration of haemopoietic of circulating neoplastic cells in mycosis progenitors; VLA-4 is expressed on T cell fungoides/Sézary syndrome; lymphoma and permits their adhesion to VCAM-1 cells in other types of T-cell lymphoma on activated endothelium and subsequent β α β may also fail to express CD26 transmigration; 1 integrins ( 2 1 and α β CD27 a member of the tumour necrosis 3 1) are expressed on thymic epithelial factor receptor superfamily which exists cells and mediate adhesion of thymo- as a homodimer; expressed on some T cytes; expressed on basophils; expressed cells, memory B cells (but not immature on normal mast cells or mature but naïve B cells) and NK cells; Expressed on neoplastic mast cells; an early activation marker on T cells; the VLA-4 is expressed in follicular lym- ligand for CD27 is CD70 which belongs phoma. VLA-3 is expressed at high levels to the tumour necrosis family; binding in chronic lymphocytic leukaemia of CD70 to its ligand, in the presence of CD30 a cell surface antigen (initially interleukin-2, increases differentiation of recognized by the Ki-1 monoclonal anti- memory B cell to plasma cells; the cyto- body), a member of the nerve growth plasmic tail of CD27 can bind to a fas-like receptor superfamily expressed on activ- molecule, Siva, which in turn induces ated B cells and T cells; on T cells is a late apoptosis; expressed on the cells of poly- activation marker; binds to CD153 on clonal B-cell lymphocytosis, which may neutrophils, activated T cells, monocytes be an expansion of memory B cells; and macrophages; weakly expressed on expressed by normal plasma cells late erythroid cells and late cells of granu- CD27 is often expressed on neoplastic locyte lineage, expressed on plasma cells B cells, e.g. in most cases of chronic lym- CD30 is strongly expressed on Hodgkin’s phocytic leukaemia, three-quarters of cases cells and Reed–Sternberg cells (except of follicular lymphoma and two-thirds of in nodular lymphocyte predominant cases of diffuse large B-cell lymphoma; Hodgkin’s disease), elevated levels of more likely to be expressed by plasma serum CD30 correlating with poor cells in monoclonal gammopathy of unde- prognosis; strongly expressed on the termined signiﬁcance than by myeloma lymphoma cells of systemic anaplastic cells; when expressed on neoplastic B large cell lymphoma (but not cutaneous cells, is often co-expressed with its ligand anaplastic large cell lymphoma) and may CD28 a member of the immunoglobulin be weakly expressed on the cells of other superfamily of cell surface molecules types of large cell non-Hodgkin’s lym- which allows T cells to proliferate in the phoma; expressed on cells of about a presence of phorbol esters; exists as a third of cases of transformed mycosis homodimer, which binds to co-stimula- fungoides; expressed by some carcinomas tory receptors such as CD80 and CD86 and some germ cell tumours; CD30 on antigen-presenting cells; expressed on monoclonal antibodies linked to mag- mature thymocytes, most T cells, activ- netic microbeads have been used experi- ated B cells and plasma cells mentally for the isolation of mononuclear β CD29 a glycoprotein, platelet GpIIa; 1 Hodgkin’s cells and Reed–Sternberg cells integrin chain; the β chain of VLAs (very CD31 a cell surface glycoprotein, Platelet/ late activation antigens) including VLA-1 Endothelial Cell Adhesion Molecule (CD49a/CD29), VLA-2 (CD49b/CD29), (PECAM-1); an adhesion molecule of VLA-3 (CD49c/CD29) and VLA-4 the immunoglobulin gene superfamily (CD49d/CD29); VLA-2 is platelet glyco- involved in homophilic and heterophilic protein IaIIa, a platelet collagen receptor; cell adhesion; activation of integrins α β VLA-4, 4 1 integrin is expressed on occurs following CD31 cross-linking; HAE-C 01/13/2005 05:10PM Page 44

44 CD32

expressed on endothelial cells, platelets, differing phagocytic capacities, providing megakaryocytes, haemopoietic progeni- a mechanism for heritable susceptibility tors, monocytes, macrophages, neutrophils, to immune complex disease; certain poly- eosinophils, NK cells, a subset of T cells morphisms in FcγRII are associated with and plasma cells; mediates binding of an increased incidence of lupus nephritis CD34-positive haemopoietic precursors CD32 is often expressed in acute cells to stroma; on platelets, it is a nega- myeloid leukaemia, more often in M4 tive regulator of aggregation induced by and M5 categories but not with sufficient collagen; expressed on endothelial cells specificity for this to be diagnostically including those of the bone marrow; has useful a role in the transendothelial migration CD33 Sialic acid-binding Immunoglobulin- of neutrophils and monocytes; CD31 on like Lectin 3, siglec-3; a sialic acid- high endothelial cells is a ligand for CD38 dependent adhesion molecule expressed on T cells; interacts with αvβ3 integrin on on myeloblasts, promyelocytes and myelo- endothelial cells and a subset of T cells; cytes and expressed weakly on mature CD31 on endothelial cells is up-regulated neutrophils; expressed more strongly on by verotoxin, promoting adhesion of monocytes than neutrophils; expressed platelets; increased phosphorylation of on some dendritic cells, which are viewed PECAM-1 on endothelial cells follow- as being of myeloid origin, but not on ing interaction with erythrocytes of others viewed as being of lymphoid ori- sickle cell anaemia leads to increased gin; sometimes expressed on basophils transendothelial migration of monocytes; and usually expressed on mast cells; thought to be a minor histocompatibility expressed on some NK cells antigen, well defined polymorphism of CD33 is expressed on the blast cells of which increase the risk of acute graft- the majority of cases of acute myeloid versus-host disease following bone mar- leukaemia, being particularly strongly row transplantation expressed on cells of M3 and M5 acute CD31 is expressed on plasma cells myeloid leukaemia; may be weakly ex- in monoclonal gammopathy of undeter- pressed in acute lymphoblastic leukaemia; mined significance and on plasma cells anti-CD33 monoclonal antibodies, some of plasmacytic multiple myeloma but coupled to an antitumour antibiotic or a much less often expressed in plasma- radionucleide, e.g. gentuzumab ozogam- blastic multiple myeloma and plasma icin (Myelotarg), are of potential thera- cell leukaemia; expressed in benign and peutic value in acute myeloid leukaemia malignant tumours of vascular origin, in and myelodysplastic syndromes histiocytic sarcoma and occasionally in CD34 a monomeric cell surface glycopro- other tumours tein, a cell adhesion molecule expressed CD32 a cell surface glycoprotein, a low on lymphoid and haemopoietic stem affinity IgG receptor—FcγRII; expressed cells, and used for selection of haemopoi- on monocytes, macrophages, Langerhans etic stem cells; expressed on the earliest cells, neutrophils, eosinophils, platelets, identifiable mast cell precursors; expres- mast cells, B cells and placental endothe- sed on endothelial cells including those of lial cells; expressed on NK cells of some the bone marrow; expression on high individuals; there are two different recep- endothelial cells of lymph node veins per- tors detected by antibodies of this clus- mits binding to endothelium by lympho- ter, FcγRIIA (expressed on neutrophils, cytes expressing L-selectin (CD62L), the eosinophils, macrophages and platelets) lymphocyte homing receptor and FcγRIIB (expressed on neutrophils, CD34 is expressed on the blast cells of macrophages, mast cells and B cells); the most cases of acute myeloid leukaemia, cytoplasmic tail of the molecule is essen- many cases of B-lineage acute lympho- tial for the formation of phagolysosomes; blastic leukaemia (pro-B and common allelic variants of the Fcγ receptor confer but not pre-B or mature B) and some HAE-C 01/13/2005 05:10PM Page 45

CD38 45

cases of T-lineage acute lymphoblastic bral malaria whilst others confer protec- leukaemia tion against malaria; CD36 deficiency is CD35 a single chain cell surface glyco- present in at least 2 to 3% of Japanese, protein existing in four allotypic forms Thais and Africans but in less than 0.3% (A,B,C,D): C3b/C4b complement recep- of Caucasians and can be involved in tor (CR1); expressed by erythroid some cases of isoimmune neonatal cells, neutrophils, eosinophils, basophils, thrombocytopenia and refractoriness to monocytes, B cells and 10–15% of T cells; transfusion of HLA-matched platelets; not expressed on normal mast cells; antibodies to CD36 are detected in the expressed on follicular dendritic cells but majority of cases of thrombotic thrombo- not Langerhans cells or interdigitating cytopenic purpura and in a significant dendritic cells; mediates phagocytosis; proportion of cases of autoimmune has a role in splenic clearance of comple- thrombocytopenic purpura and heparin- ment coated erythrocytes; binds to C3b induced thrombocytopenia; they may and C4b in immune complexes and pro- also contribute to thrombosis in patients motes their clearance; mediates adhesion with the lupus anticoagulant to and phagocytosis of complement- CD36 is expressed on megakaryoblasts coated particles; makes C3b and C4b in M7 acute myeloid leukaemia and some more susceptible to cleavage; expressed cases of M4, M5 and M6 acute myeloid on glomerular podocytes; CD35 carries leukaemia the Knops blood group antigens; permits CD37 MB-1, a member of the transmem- entry of HIV into cells brane 4 or tetraspanin superfamily of pro- CD35 is often expressed in acute teins, involved in signal transduction; forms myeloid leukaemia, more often in M4 complexes with CD53, CD81, CD82 and and M5 categories but not with sufficient MHC class II molecules on the surface of specificity for this to be diagnostically B cells; strongly expressed on mature B useful; may be expressed on neoplastic cells but expressed weakly on T cells, neu- mast cells both in systemic mastocytosis trophils and monocytes so that strong and in acute mast cell leukaemia; expression can be used a B-cell marker expressed in non-Hodgkin’s lymphoma CD37 may be expressed on late B lym- but not usually expressed by chronic lymphoblasts that also express cytoplasmic µ phocytic leukaemia cells chain but not on more immature B lym- CD36 a trans-membrane protein, platelet phoblasts; monoclonal antibodies linked glycoprotein IV, thrombospondin recep- to a radionucleide have been used in the tor, fatty acid translocase; expressed on therapy of B-cell neoplasms megakaryocytes and platelets; expressed CD38 a transmembrane glycoprotein, on erythroblasts, fetal red cells, mono- NAD+ glycohydrolase/ADP-ribosyl cytes, macrophages, microvascular endo- cyclase which has ectoenzymatic activity thelium, retinal pigment epithelial cells but also functions as a receptor with a and adipocytes; has a role in platelet role in cell adhesion and signalling; aggregation, cell adhesion, inhibition expressed on thymic cells, early B and T of angiogenesis and recognition and cells, germinal centre B cells, some T removal of apoptotic cells; mediates scav- cells (most tissue T cells but a minority enging of oxidized low density lipopro- of peripheral blood T cells; expressed tein by macrophages; involved in creation by naïve CD45RA+ T cells but not of foam cells in early atherosclerosis; CD45RO+ memory T cells), activated CD36 binds erythrocytes parasitized by NK cells, a subset of monocytes (but not P. falciparum thus contributing to their tissue macrophages), osteoclasts, plasma sequestration and survival and to the cells, haemopoietic progenitors, baso- pathology of the disease (e.g. cerebral phils but not mast cells, red cells and malaria); some polymorphisms in the platelets; pancreatic β cells—where CD36 gene enhance susceptibility to cere- expression is essential for insulin secre- HAE-C 01/13/2005 05:10PM Page 46

46 CD39

tion, neurones, Purkinje cells, astrocytes on T cells (CD40L, CD154) and this and neurofibrillary tangles in Alzheimer’s drives B-cell proliferation; expressed on disease, retinal cells, renal tubular cells, B cells and precursors, but not on the prostatic epithelium and sarcolemma of most immature B lymphoblasts, and is smooth and striated muscles; binds to involved in growth, differentiation and extracellular matrix; binds to CD38 lig- isotype switching of B cells, T-cell- and (CD31) on high endothelial cells, T- dependent B-cell responses and rescue of cell subsets, NK cells, monocytes and germinal centre B cells from apoptosis; platelets; in HIV infection, the number of expressed weakly on plasma cells; also CD8+CD38+ T cells increases with pro- expressed on T cells, activation leading to gression to AIDS with the expression of increased expression of its ligand and CD38 on CD8+ T cells being of indepen- secretion of cytokines and chemokines dent prognostic significance including IL1, IL6, IL8, IL12, IL15; CD31 binding to CD38 leads to apop- expressed on CD34+ haemopoietic pro- tosis of bone marrow B cells but protects genitors, monocytes, (but not those in tonsillar B cells from apoptosis and leads cord blood), macrophages, platelets, to proliferation of splenic B cells endothelial cells, fibroblasts and some CD38 is expressed on myeloma cells, epithelial cells; variably expressed on nor- on cells of primary effusion lymphoma, mal and neoplastic mast cells; expressed on cells of some cases of splenic lym- weakly on immature dendritic cells, such phoma with villous lymphocytes and as those in skin and other peripheral tis- some cases of chronic lymphocytic sues, but expressed strongly on mature leukaemia; in multiple myeloma, expres- follicular dendritic cells in lymph nodes; sion correlates with a worse prognosis; in has a role in cytokine production by chronic lymphocytic leukaemia, expres- macrophages and dendritic cells sion correlates with clonal origin from a Expressed in B-cell tumours including less mature cell and with worse prognosis; acute lymphoblastic leukaemia; expres- expressed in acute myeloid leukaemia sed on Reed–Sternberg cells and Hodgkin’s and acute lymphoblastic leukaemia, strong cells in lymphocyte predominant and expression in acute myeloid leukaemia classical Hodgkin’s disease; expressed, correlating with better prognosis together with CD40 ligand, on cells of Expression of CD38 on myeloid cells some cases of non-Hodgkin’s lymphoma is up-regulated by all-trans-retinoic acid (mantle cell lymphoma and follicular (ATRA) and is likely to lead to binding of lymphoma) so that an autocrine cytokine leukaemic cells to CD31 on endothelial loop could occur; similarly co-expressed, cells in the ATRA syndrome and in the with its ligand, in cells of some cases of similar syndrome induced by arsenic chronic lymphocytic leukaemia; expressed in patients with acute promyelocytic in the majority of cases of Langerhans leukaemia cell histiocytosis; may be expressed in CD39 ATP diphosphohydrolase, ex- acute myeloid leukaemia and expres- pressed on the surface of vascular endo- sion correlates with worse prognosis; thelium and essential for the hydrolysis expressed on carcinoma cells of extracellular ATP to ADP and AMP CD41a platelet glycoprotein IIb/IIIa in platelet recruitment and adhesion; complex (αIIbβ3 integrin); the genes expressed on activated B cells, activated encoding both αIIb and β3 integrins are NK cells, some macrophages, some at 17q21.32 but are not closely linked; dendritic cells and some plasma cells; expressed on megakaryocytes and plat- CD39 is expressed on chronic lympho- elets; involved in the increased inter- cytic leukaemia cells action of platelets with endothelium CD40 a cell surface glycoprotein, a mem- on exposure to verotoxin; has a role ber of the tumour necrosis factor receptor in megakaryocyte-dependent fibroblast superfamily; interacts with CD40 ligand growth; receptor for von Willebrand’s HAE-C 01/13/2005 05:10PM Page 47

CD43 47

factor, fibronectin, fibrinogen and throm- being associated with CD42a and CD42d; bospondin; mutations in the genes for mutations of the CD42b gene can cause both platelet glycoprotein IIb and IIIa Bernard–Soulier syndrome and platelet- have been shown to be associated with type von Willebrand’s disease in which different types of Glanzmann’s thrombas- the platelets have increased affinity for thenia; not expressed on normal mast von Willebrand’s factor, as a result of a cells; monoclonal antibodies to glyco- gain of function mutation; polymorphisms protein IIb/IIIa are used therapeutically of CD42b have been related to arterial as potent antithrombotic agents, e.g. in thrombosis; has a role in megakaryocyte- patients having coronary angioplasty dependent fibroblast growth; not Expressed on megakaryoblasts of M7 expressed on normal mast cells acute myeloid leukaemia; may be ex- CD42b may be expressed, but usually pressed on neoplastic mast cells only weakly, by megakaryoblasts of CD41b platelet glycoprotein IIb; forms a M7 acute myeloid leukaemia; positivity β heterodimer with 3 integrin (CD61) with in acute myeloid leukaemia is usually the α β the heterodimer ( IIb 3) being expressed result of adherent platelets; may be on multipotent myeloid stem cells (CFU- expressed on neoplastic mast cells GM), bipotent erythroid–megakaryocyte CD42d platelet glycoprotein Ibβ; forms a stem cells, megakaryocyte colony- heterodimer with CD42b and binds non- forming cells (CFU-MK), megakaryo- covalently with CD42a and CD42d to cytes and platelets; mediates binding of form the CD42a-d receptor complex; haemopoietic stem cells to stromal fib- mutation of the CD42c gene can lead to ronectin; mediates platelet adhesion to Bernard–Soulier syndrome subendothelial matrix and platelet CD42e platelet glycoprotein V, part of aggregation induced by fibrinogen, von the CD42a-d complex; although the Willebrand’s factor, thrombin, collagen, actual binding site is on CD42b, the ADP and adrenaline; polymorphisms in presence of CD42e is necessary in order CD41b are responsible for the HPA3 for the complex to provide a strong platelet alloantigen system thrombin-binding site CD41b is expressed on megakary- CD43 a mucin-like, heavily glycosyl- oblasts of M7 acute myeloid leukaemia ated and heavily sialylated glycoprotein, CD42a platelet glycoprotein IX; ex- sialophorin or leukosialin, expressed on pressed on megakaryocytes and platelets; T lymphocytes, occasionally on activated the CD42a-d (or GpIb-IX-V) complex is B cells; expressed on myeloid cells includ- the platelet receptor for von Willebrand’s ing haemopoietic progenitors; expressed factor and thrombin; it mediates adhesion on basophils and mast cells; in some to the subendothelium which in turn circumstances inhibits adhesion and in causes platelet activation and converts other circumstances may promote it; α β IIb 3 (see CD41b) from a low affinity CD43 is an anti-adhesive molecule in to a high affinity state; the response to resting leucocytes and is down-regulated thrombin and other agonists is thereby on activation; has a role in neutrophil enhanced; mutations of the CD42a gene locomotion; CD43 has a role in activa- can cause Bernard–Soulier syndrome tion of T cells, B cells, NK cells and CD42a is expressed on megakary- monocytes; it is aberrantly glycosylated oblasts of M7 acute myeloid leukaemia in Wiskott–Aldrich syndrome; CD54 is a CD42b platelet glycoprotein Ibα; ex- ligand for CD43 pressed on megakaryocytes and platelets; CD43 is expressed in T-lineage acute CD42a-d complex is the platelet receptor lymphoblastic leukaemia and T-lineage for von Willebrand’s factor and thrombin, non-Hodgkin’s lymphoma, chronic lym- the actual binding site being on the CD42b phocytic leukaemia, small lymphocytic molecule; CD42b forms a heterodimer lymphoma, mantle cell lymphoma and with CD42c with the heterodimer also Burkitt’s lymphoma but rarely in follicu- HAE-C 01/13/2005 05:10PM Page 48

48 CD44

lar lymphoma; expressed in a proportion neutrophils but eosinophils show similar of lymphoplasmacytoid lymphomas and expression to monocytes; strongly ex- marginal zone lymphomas; may be pressed on T and B lineage lymphocytes; expressed by neoplastic mast cells necessary for receptor-mediated activa- CD44 a transmembrane protein ex- tion of T and B cells; augments signalling pressed as a family of multiple isoforms through antigen receptors on T and B generated by alternative RNA splicing; cells; different isoforms exist formed by it is an adhesion molecule (CD44H, differential splicing of exons 4, 5 and 6 to H-CAM); expressed on all blood cells, give CD45RA, CD45RB and CD45RC except platelets, and in non-haemopoietic respectively as well as CD45RO (lacking tissues; expressed on haemopoietic stem any of exons 4, 5 or 6); CD45 is the cells and may mediate binding to hyalur- common epitope; expressed on tonsillar onate; expressed on mast cells as well plasma cells and on reactive plasma cells as basophils; expressed on macrophages produced in response to increased IL6 and osteoclasts; expressed on plasma secretion, but weakly expressed if at all cells, expressed on ﬁbroblasts and some on normal bone marrow plasma cells; epithelial cells; CD44 has a role in neu- expressed by mast cells; follicular den- trophil attachment to endothelial cells, dritic cells are CD45− development of cytotoxicity and genera- CD45 is strongly expressed on T and tion of IL6 and in lymphocyte homing B lineage lymphoblasts in most cases and development of lymphocyte cytotox- of acute lymphoblastic leukaemia; more icity; it may have a role in the attachment strongly expressed in T-lineage acute of haemopoietic stem cells to stroma; lymphoblastic leukaemia than B-lineage expressed on white matter of brain; CD44 acute lymphoblastic leukaemia and is not expressed in normal liver but is about 20% of cases of B-lineage acute expressed in bile duct epithelium in some lymphoblastic leukaemia are negative; bile duct diseases; it probably has a role in weakly expressed on blast cells of acute autoimmune biliary disease, by promot- myeloid leukaemia; expressed by neo- ing lymphoepithelial interactions; CD44 plastic mast cells; Hodgkin’s cells and carries the Indian blood group antigens Reed–Sternberg cells of classical CD44 is expressed on multiple mye- Hodgkin’s disease are CD45− but neo- loma cells; it is expressed on most lym- plastic cells of nodular lymphocyte pre- phoma cells, particularly those of low dominant Hodgkin’s disease are positive; grade lymphoma and increased levels sometimes expressed by myeloma cells; of serum CD44 have been found of pro- radiolabelled CD45 antibodies may be gnostic signiﬁcance; expressed normally useful in eliminated neoplastic cells prior on chronic lymphocytic leukaemia cells; to stem cell transplantation expressed by neoplastic mast cells; certain CD45RA a high molecular weight iso- splice variants of the CD44 gene are over- form of the leucocyte common antigen, represented in several human carcino- expressed on haemopoietic progenitors, mas, where they may indicate increased B cells, naïve T cells and monocytes; likelihood of tumour progression expressed in most B-lineage neoplasms CD45 the leucocyte common antigen—a CD45RB an isoform of the common protein-tyrosine phosphatase, receptor- leucocyte antigen, expressed on B cells, a type, c-ptprc, that removes phosphate T-cell subset, monocytes, macrophages groups from tyrosine residues of target and neutrophils proteins, expressed on all haemopoietic CD45RC a high molecular weight iso- cells except mature red cells and their form of the leucocyte common antigen, immediate precursors; expressed on early expressed on B cells and a T-cell subset; cells of neutrophil lineage but expres- monoclonal antibodies may recognize a sion diminishes with maturation; more sialylated form of the sequence encoded strongly expressed on monocytes than by the C exon HAE-C 01/13/2005 05:10PM Page 49

CD49d 49

CD45RO a low molecular weight isoform to glycosylphosphatidylinositol (GPI) of the leucocyte common antigen, ex- and is therefore reduced in paroxysmal pressed on neutrophils, a B-cell subset, nocturnal haemoglobinuria T-cell subsets (memory T cells), mono- CD49a a membrane glycoprotein, α1 cytes, macrophages; expressed weakly integrin chain and strongly, respectively, on two subsets CD49b a membrane glycoprotein, α2 α β of thymic dendritic cells integrin; integrin 2 1 (very late antigen- CD45RO is expressed in T-cell 2, VLA-2) is platelet glycoprotein Ia/IIa lymphomas but also in some B-cell (CD49b/CD29) which mediates adhe- lymphomas sion of mature megakaryocytes and α β CD46 a dimeric cell surface membrane platelets to collagen; 2 1 integrins are protein, Membrane Cofactor Protein also expressed on thymic epithelial cells, (MCP) acting as a cofactor for prote- B cells, activated T cells, monocytes, olytic cleavage of C3b and C4b; ubiqui- endothelial cells and fibroblasts; the α2 tous—expressed on all nucleated cells gene is polymorphic, leading to lesser or (not erythrocytes); receptor for the greater expression of IaIIb on platelets; measles virus; CD46 is incorporated into VLA-2 is a principal vector used by neu- the HIV envelope and protects the virus trophils for locomotion in extravascular and HIV-infected cells against comple- tissues; permits coxsackie and aden- ment deposition oviruses to enter cells CD47 an adhesion molecule, integrin- CD49c a membrane glycoprotein, α3 α β associated protein; thrombospondin integrin chain; 3 1 integrin (very late receptor and receptor for transmembrane antigen-3, VLA-3) is expressed on thymic Signal Regulatory Protein alpha (hence epithelial cells and mediates adhesion of SIRP ligand)—an inhibitory receptor thymocytes to thymic epithelium; expres- expressed on myeloid cells; CD47 is sed on B cells, monocytes, platelets and expressed on many cell types including kidney glomerular cells; usually expres- haemopoietic cells; it is a glycoprotein sed on chronic lymphocytic leukaemia component of the Rh protein complex; cells although they fail to express CD29 knockout studies in mice have shown CD49d a membrane glycoprotein, α4 α β CD47 to be important in neutrophil integrin chain; 4 1 integrin (very late migration in response to bacterial infec- activation antigen-4, VLA-4) permits tion; thrombospondin forms a bridge adhesion of megakaryocyte-colony form- between apoptotic cells and phagocytes ing units and immature megakaryocytes by binding of CD47 to CD36 to fibronectin, adhesion of bone marrow Binding of either thrombospondin or progenitor cells to fibronectin of base- CD47 antibodies to CD47 in chronic ment membrane and adhesion of haemo- lymphocytic leukaemia can induce cell poietic progenitor cells to VCAM-1 on death bone marrow stromal cells and activ- CD47R redesignation of CDw149, MEM- ated endothelial cells; VLA-4-mediated 133; expressed on lymphocytes and adhesion of progenitor cells to basement monocytes membrane and bone marrow endothelial CD48 a surface membrane glycoprotein cells may permit transendothelial and closely related to the activation protein, trans-basement membrane migration of α β Blast-1; a member of the Ig supergene progenitor cells; 4 1 integrin (VLA-4) per- family, expressed on monocytes and mits adhesion of eosinophils to VCAM-1 almost all T cells and B cells; expressed on (CD106) of endothelial cells; expressed EBV-induced B-lineage blasts; ligand of on basophils; expressed on normal and α β α β CD244; a weak binder of CD2 and there- neoplastic mast cells; 4 1 and 4 7 fore acts as an adhesion molecule and as a integrins mediate adhesion of normal costimulatory molecule for T cells; has a B cells and B-lineage lymphoma cells role in graft-versus-host disease; is bound to fibronectin and may promote their HAE-C 01/13/2005 05:10PM Page 50

50 CD49e

α α proliferation; VLA-4 is expressed on CD51 v integrin chain, the chain of α β plasma cells the vitronectin receptor, v 3 integrin CD49d/CD29 (VLA-4) is expressed on (CD51/CD61); the vitronectin receptor myeloma cells, follicular lymphoma cells is expressed on platelets, macrophages, and neoplastic mast cells osteoclasts and endothelial cells; upregu- CD49e a membrane glycoprotein, α5 lated on endothelial cells after exposure α β integrin chain; 5 1 integrin (very late to verotoxin; expressed on mast cells; α β antigen-5, VLA-5) is expressed on mature v 3 integrin is also expressed on late megakaryocytes and strongly promotes megakaryocytes and may aid their adhe- α β their adhesion to fibronectin; promotes sion to vitronectin; v 3 is expressed on adhesion of thrombin stimulated mega- neutrophils, permitting their binding to α karyocytes to fibrinogen; VLA-5 is ex- vitronectin and their locomotion; v can β β β pressed on neutrophils and mediates also pair with 5, 6 and 8 their binding to fibronectin of connective CD51 is expressed by neoplastic mast tissue and their locomotion; VLA-5 is cells expressed on haemopoietic progenitor CD52 a glycosylphosphatidylinositol (GPI)- cells and, since it binds to fibronectin, anchored protein, reduced in paroxysmal may permit their migration through base- nocturnal haemoglobinuria; expressed on ment membrane; expressed on plasma thymocytes, lymphocytes, eosinophils, cells; expressed on mast cells monocytes and macrophages (but not VLA-5 is expressed on neoplastic mast neutrophils), and epithelial cells of the cells; it is usually expressed by chronic epididymus and seminal vesicles; expres- lymphocytic leukaemia cells although sion by chronic lymphocytic leukaemia they fail to express CD29; expressed on cells is similar to that of normal lympho- myeloma cells cytes; antibodies to CD52, e.g. alem- CD49f a membrane glycoprotein, α6 tuzumab (CAMPATH-1), can give α β integrin chain; 6 1 integrin (very late long-term depletion of T lymphocytes antigen-6, VLA-6) is expressed on when used in vivo and can be used for megakaryocytes, platelets, most epithe- purging T lymphocytes in vitro; a combi- lial cells, monocytes and T lymphocytes; nation of CAMPATH-1M for in vitro expression on thymic epithelial cells purging and CAMPATH-1G adminis- mediates adhesion of thymocytes; expres- tered to the recipient has been used to sion on megakaryocytes mediates their reduce graft-versus-host disease without α β binding to laminin; 6 1 integrin is a concomitant increase in failure of expressed on the Th1 subset of helper T engraftment lymphocytes, expression being upregu- Alemtuzumab is useful in T-prolym- lated by IL-12 phocytic leukaemia, may be useful in CD50 ICAM-3 (Intercellular Adhesion eliminating minimal residual disease in B- Molecule-3), an adhesion and co- lineage chronic lymphocytic leukaemia stimulatory molecule, a member of he and can be used for in vivo purging for immunoglobulin superfamily of adhesion autologous stem cell transplantation in receptors, expressed on immature and chronic lymphocytic leukaemia mature leucocytes and dendritic cells; a CD53 OX44, a member of the transmem- β ligand for the 2 integrin CD11a/CD18 brane 4 or tetraspanin superfamily of α and for d/CD18; plays a role in the inter- proteins, expressed on leucocytes, has a action of T lymphocytes with antigen- role in signal transduction; structurally presenting cells similar to and forms complexes with CD50 is expressed on cells of acute CD37 and chronic myeloid leukaemias, chronic CD54 a cell surface glycoprotein, ICAM- lymphocytic leukaemia, hairy cell leuk- 1 (Intercellular Adhesion Molecule-1), an aemia, multiple myeloma and non- adhesion molecule that is a ligand for β Hodgkin’s lymphoma 2 integrins, CD11a/CD18 and CD11b/ HAE-C 01/13/2005 05:10PM Page 51

CD57 51

CD18; expressed on activated endothelial The Cromer blood group system cells including those of the bone marrow, consists of antigens carried on the DAF activated B lymphocytes and activated molecule: in the rare Inab phenotype, T lymphocytes; expressed on dendritic all Cromer system antigens are lacking; cells, permitting their binding to CD11a this has been associated with mutations on T cells; up-regulated on microvascular in the DAF gene resulting in a complete endothelial cells following exposure to absence of DAF; such individuals are verotoxin, promoting neutrophil adhe- not known to have any associated sion; expressed on macrophages and osteo- abnormalities clasts; functions as a rhinovirus receptor; CD56 an isoform of N-CAM, Neural Cell permits adhesion and transendothelial Adhesion Molecule, a member of the migration of VLA-4-expressing haemo- immunoglobulin superfamily, expressed poietic progenitors; activated eosinophils on cells in the cerebellum and cerebral express β2 integrins, permitting their cortex (neurones, astrocytes and Schwann adhesion to ICAM-1 on endothelial cells; cells), mediates homophilic adhesion of expression of ICAM-1 is increased when neural cells; expressed on NK cells (mature the erythrocytes of sickle cell anaemia and immature but not pre-NK cells), a adhere to endothelium; binds erythro- subset of CD4+ T cells and a subset cytes parasitised by P. falciparum thus of CD8+ T cells; expressed on activated contributing to their sequestration and lymphocytes; expressed on a subset of survival and to the pathology of the peripheral blood monocytes and bone disease (e.g. cerebral malaria); polymor- marrow macrophages and osteoclasts; phisms in the CD54 gene may predispose not expressed on normal plasma cells to cerebral malaria; expressed on basophils CD56 is usually expressed in large and mast cells; expressed on circulating granular lymphocyte leukaemia of NK dendritic cells; expressed on plasma cells lineage and sometimes in large granular CD54 is expressed on neoplastic mast lymphocyte leukaemia of T-cell lineage; cells; expressed on myeloma cells; ex- expressed on blastic NK cell leukaemia/ pressed on the blast cells of about three- lymphoma, aggressive NK cell leukaemia/ quarters of patients with acute myeloid lymphoma and nasal-type NK cell lym- leukaemia; serum CD54 is of prognostic phoma; expressed on the cells of many significance in non-Hodgkin’s lymphoma patients with acute myeloid leukaemia; and in high grade lymphoma correlates expressed in many cases of multiple with tumour burden; soluble CD54 is myeloma and somewhat less often in increased in chronic lymphocytic leuk- plasma cell leukaemia; may promote aemia although it is not expressed on the homotypic adhesion of myeloma cells leukaemic cells to bone marrow macrophages; down- CD55 a glycosylphosphatidylinositol regulated on extramedullary myeloma (GPI)-linked cell surface glycoprotein, cells in comparison with bone marrow decay accelerating factor (DAF), binds myeloma cells; according to some studies, C3b, C4b, C3bBb, C4b2a and protects not expressed on the plasma cells of mon- against inappropriate complement activa- oclonal gammopathy of undetermined tion; widely expressed including expres- significance; expressed on the cells of small sion on erythroid cells; reduced expression cell carcinoma of the lung and neural- in paroxysmal nocturnal haemoglobinuria derived tumours such as neuroblastoma (PNH); ligand for CD97; CD55 anti- and astrocytoma; CD56 expression has bodies can be used to identify cells of the been linked to a worse prognosis in PNH clone; CD55-deficient red cells have acute myeloid leukaemia associated with also been detected in a proportion of t(8;21) and t(15;17) patients with lymphoproliferative dis- CD57 a carbohydrate determinant found orders; receptor for echovirus, coxsackie on a number of polypeptides and lipids; virus, picornaviruses and enterovirus expressed on NK cells, subsets of T cells, HAE-C 01/13/2005 05:10PM Page 52

52 CD58

B cells, monocytes and a subset of sed including expression in erythrocytes, Schwann cells neutrophils, lymphocytes, monocytes, CD57 is usually expressed on large platelets and mast cells; has a signalling granular lymphocyte leukaemia of T-cell role in T-cell activation; is incorporated lineage and sometimes in large granular into the HIV envelope and protects the lymphocyte leukaemia of NK lineage virus and HIV-infected cells against com- CD58 a glycoprotein that occurs as a plement deposition transmembrane protein with a cytoplasmic CD59 is expressed on neoplastic mast domain and as a glycosylphosphatidyli- cells nositol (GPI)-anchored membrane protein; CD60 a glycolipid which provides costim- Leucocyte Function Associated antigen-3 ulatory signals for T cells; expressed on a (LFA-3), the ligand of CD2, expressed on subset of CD8+ T cells, platelets, thymic leucocytes, dendritic cells, erythrocytes, epithelium, glomeruli, smooth muscle endothelial cells, epithelial cells and cells and astrocytes; revised classification fibroblasts; expressed on a proportion of as CD60a, CD60b and CD60c lymphoid stem cells; not expressed on CD60a a glycolipid, GD3 normal plasma cells; mediates adhesion CD60b a glycolipid, 9-O-acetyl-GD3 between killer cells and their targets, CD60c a glycoclipid, 7-O-acetyl-GD3 between antigen-presenting cells and T CD61 a surface membrane glycoprotein, cells and between thymocytes and thymic the β3 integrin chain, GpIIIa; part of α β epithelium; provides costimulatory sig- the GpIIb/IIIa complex, IIb 3 integrin; nals in immune responses; expressed by expressed on platelets and megakary- mast cells; reduced expression in paroxys- ocytes (in association with CD41) and mal nocturnal haemoglobinuria (PNH) on monocytes, macrophages, osteoclasts, CD58 is expressed on blast cells in the endothelial cells and platelets (in associa- majority of cases of acute myeloid leuk- tion with CD51, forming the vitronectin aemia and B-lineage acute lymphoblastic receptor, CD51/CD61); expressed on leukaemia; expressed by neoplastic mast mast cells; GpIIb/IIIa is a receptor for cells and may permit adhesion of neoplas- fibrinogen, fibronectin, vitronectin and tic mast cells showing aberrant expres- von Willebrand’s factor; a point mutation sion of CD2 to each other; expressed on in the CD61 gene results in Glanzmann’s myeloma cells thrombasthenia type B; polymorphisms in CD59 a glycosylphosphatidylinositol CD61 are responsible for the HPA1 and (GPI)-linked cell surface glycoprotein, HPA4 platelet alloantigen systems MIC11, which associates with the final Expressed on blast cells of M7 acute component of the complement pathway, myeloid leukaemia and may be expressed C9, inhibiting incorporation of C5b-8 to weakly by leukaemic cells of other sub- form a membrane attack complex (hence types of acute myeloid leukaemia; CD61 ‘protectin’); reduced in paroxysmal noc- is expressed on neoplastic mast cells turnal haemoglobinuria, a disease which CD62E E selectin, Endothelium Leucocyte is characterized by abnormal comple- Adhesion Molecule (ELAM-1, LECAM- ment sensitivity; CD59 antibodies can be 2), expressed on activated endothelium used to identify cells of the PNH clone; and mediates rolling of neutrophils, mono- CD59-deficient red cells have also been cytes and lymphocytes at sites of inflam- identified in a proportion of patients with mation; expression of E selectin occurs lymphoproliferative disorders; a patient after stimulation by lipopolysaccharide doubly heterozygous for different non- and inflammatory cytokines such as IL1 sense mutations in the CD59 gene leading and tumour necrosis factor; up-regulated to CD59 deficiency has been reported to by exposure to verotoxin, promoting have haemolytic anaemia and thrombosis neutrophil adhesion; a lack of expression causing cerebral infarction, but none of of E-selectin on endothelial cells has been the other features of PNH; widely expres- linked to recurrent infections in a child, HAE-C 01/13/2005 05:10PM Page 53

CD64 53

probably caused by impaired adhesion of rolling of neutrophils and eosinophils on neutrophils to endothelium; certain poly- activated endothelium; mediates adher- morphisms in CD62E are associated with ence of lymphocytes and monocytes to a early onset coronary artery disease; also lesser extent; upregulated on microvascu- expressed on proliferating endothelial lar endothelial cells by exposure to vero- cells; a ligand for CD162 (cutaneous toxin, promoting adhesion of platelets; leucocyte antigen) which is expressed on expressed on megakaryocytes and lymphocytes; mediates eosinophil adhe- mediates adhesion to fibroblasts; binds sion to endothelial cells but is less efficient to CD162 on lymphocytes and CD24 at this than P selectin; polymorphisms on neutrophils and B lymphocytes; P- in E selectin have been associated with selectin expression is reduced on the premature atherosclerosis; expression of endothelial cells of premature babies, a E-selectin is increased when the erythro- factor that may delay transendothelial cytes of sickle cell anaemia adhere to migration of neutrophils; soluble P endothelium selectin is increased in autoimmune CD62L L selectin (LECAM-1/LAM-1). thrombocytopenic purpura and follow- Expressed on B and T lymphocytes, some ing deep vein thrombosis; certain poly- NK cells, thymocytes, haemopoietic morphisms in CD62E are associated with progenitors, monocytes and neutrophils; reduced incidence of myocardial infarc- mediates homing of lymphocytes to high tion; mediates adhesion of sickle cells endothelial venules of peripheral lym- to endothelium; binds to a protein that phoid tissues and rolling of leucocytes is exported to the surface of red cells (neutrophils, monocytes and lympho- infected by Plasmodium falciparum cytes) on activated endothelium at sites CD63 melanoma associated antigen 1, of inflammation; a ligand of CD34 and ME491, a member of the transmembrane CD162; the expression of CD62L on neu- 4 or tetraspanin superfamily of proteins, trophils is up-regulated by inflammatory stored in cytoplasmic granules or lyso- stimuli and down-regulated by corticos- somes of platelets, endothelial cells, teroids; expressed on megakaryocytes neutrophils, monocytes and macrophages and mediates adhesion to fibroblasts; the and is exported to the cell surface on acti- number of cells co-expressing CD34 and vation; expressed on fibroblasts, osteo- L-selectin is predictive of rapid engraft- blasts, smooth muscle cells, neural tissue ment following autologous stem cell and melanoma cells; expressed on mast transplantation cells; deficient in the platelets of CD62L is expressed on the majority Hermansky–Pudlak syndrome of leukaemic cells and in acute myeloid CD63 is expressed more strongly on leukaemia high levels of soluble CD62L neoplastic mast cells than on normal mast in the serum correlate with a worse pro- cells gnosis; expressed normally on chronic CD64 FcγRI—high affinity receptor for lymphocytic leukaemia cells IgG, expressed on monocytes, CD34+ CD62P P selectin (LECAM-3), platelet monocyte progenitors, macrophages and alpha-granule membrane protein, located activated neutrophils and eosinophils, in the storage granules of platelets and a subset of circulating dendritic cells, endothelial cells (Weibel–Palade bodies) germinal centre dendritic cells and pro- and translocated to the surface when myelocytes; expression is up-regulated by endothelial cells are activated; mobilized interferon gamma and IL10 and down- to the cell surface on platelet activation regulated by IL4; has a role in antigen and enriched in platelet microvesicles; capture for presentation to T cells, surface CD62P expression on CD41a+ antibody-dependent cellular cytotoxicity, or CD42b+ platelets can be used as a endocytosis of immune complexes and measure of platelet activation; mediates removal of abnormal cells, such as the adhesion of platelets to endothelium and erythrocytes in thalassaemia; a non- HAE-C 01/13/2005 05:10PM Page 54

54 CD65

coding mutation in the CD64 transcript but not normal B-cell precursors so can which reduces mRNA stability and hence be used for monitoring minimal residual phagocytic expression of CD64 has been disease reported; individuals with this CD64 CD66d member of the carcinoembryonic deficiency have no known abnormalities antigen family, expressed on neutrophils, CD64 expression has a high degree of function uncertain both sensitivity and specificity for the CD66e a glycoprotein which is a diagnosis of M4 and M5 acute myeloid constituent of embryonic endodermal leukaemia (although it is also expressed, epithelium, carcinoembryonic antigen, more weakly, in M3 acute myeloid glycosylphosphatidylinositol (GPI)-linked, leukaemia) expressed (weakly) by epithelial cells and CD65 a carbohydrate ceramide dode- strongly by carcinoma cells of gastroin- casaccharide, expressed on cells of granu- testinal origin; has a role in cell adhesion locyte lineage from the promyelocyte and possibly in metastasis of tumour stage onwards and, more weakly, on cells; found in the serum where is referred monocytes; a ligand for E-selectin to as carcinoembryonic antigen (CEA) CD65 is expressed on blast cells of and is used as a tumour marker many cases of acute myeloid leukaemia; CD66f pregnancy-specific glycoprotein, expression may be critical for extra- expressed in the placenta and fetal liver; vascular infiltration by leukaemic cells may protect the fetus from the maternal CD65s is the sialylated form; CD65s is immune system expressed on granulocytes and monocytes CD67 see CD66b CD65s is expressed on cells of myeloid CD68 macrosialin, a member of the fam- leukaemias; its expression appears as ily of haemopoietic mucin-like molecules CD34 expression disappears; aberrantly that includes CD34 and CD43; expressed expressed on cells of some patients with within the cytoplasm of monocytes, macro- pro-B acute lymphoblastic leukaemia phages and osteoclasts and more weakly CD66a member of the carcinoembryonic on neutrophils and basophils; expressed antigen family, also known as biliary gly- early in the neutrophil lineage, possibly coprotein I; expressed on neutrophils and before chloroacetate esterase, but expres- epithelial cells; has a role in cell adhesion sion is lost with maturation whereas and signalling in neutrophils; a receptor in the monocyte lineage it is retained; for Neisseria spp; radiolabelled mono- expressed on mast cells; expressed on clonal antibodies to CD66a, b, c and e some B lymphocytes have been used for conditioning prior to CD68 is expressed on blast cells stem cell transplantation of many patients with acute myeloid CD66b (previously CD67), biliary glyco- leukaemia and is useful for the immuno- protein, member of the carcinoembry- histochemical demonstration of myeloid onic antigen family, product of the differentiation; expressed by megakaryo- CGM6 gene; a glycosylphosphatidylinosi- cytes and in M7 acute myeloid leukaemia; tol (GPI)-anchored protein, expressed in expressed in systemic mastocytosis; ex- neutrophils and metamyelocytes and pressed weakly on cells of B-lineage acute weakly by myelocytes, has a role in cell lymphoblastic leukaemia; occasionally adhesion and signalling expressed on hairy cells and chronic CD66c member of the carcinoembryonic lymphocytic leukaemia cells; expressed in antigen family, a glycosylphosphatidyl- the majority of cases of Langerhans cell inositol (GPI)-linked expressed in neu- histiocytosis trophils and epithelial cells, has a role in CD69 a transmembrane protein that cell adhesion and signalling, expressed in functions as a signal transmitting recep- colonic carcinoma tor in the early stages of cellular activa- Expressed by cells of a subset of B- tion; not expressed on resting peripheral lineage acute lymphoblastic leukaemia blood lymphocytes but following activa- HAE-C 01/13/2005 05:10PM Page 55

CD75s 55

tion can be expressed on B cells, T cells cells; when expressed on malignant cells (particularly) and NK cells; activated there is often co-expression of the ligand, T cells which express CD69 are mainly CD27; can function as a receptor and CD8+CD45RO+; expression on T cells is facilitate proliferation of neoplastic cells; induced by IL15 and by contact with act- expressed by nasopharyngeal carcinoma ivated endothelium expressing ICAM-1; and some thymic carcinomas expression on activated T cells rapidly CD71 transferrin receptor; mediates iron declines in the absence of exogenous stim- uptake; expressed on early and late ery- uli; detection of lymphocytes expressing throid precursors and on activated B and CD69 after exposure to a speciﬁc antigen T lymphocytes and proliferating cells in can be used to demonstrate response to general; expressed on early cells of neu- that antigen; expressed on some thymo- trophil lineage but lost on maturation; cytes; constitutively expressed on mono- expressed on mast cells cytes, epidermal Langherhans cells, mast CD71 is expressed on immature cells, platelets and bone marrow myeloid erythroid cells in M6 acute myeloid precursors; expressed on activated neu- leukaemia; often expressed in T-lineage trophils and eosinophils; expressed on acute lymphoblastic leukaemia and may mantle zone B cells and some germinal be expressed in aggressive lymphomas; centre B cells and has a role in B-cell expressed on neoplastic mast cells; expres- development; expressed on mast cells sed on Reed–Sternberg cells and overexpressed in reactive mast cells CD72 an antigen expressed on B cells and in monoclonal gammopathy of undeter- B-cell precursors; ligand for CD5 and mined signiﬁcance and myelodysplastic CD100; CD72 is a negative regulator of syndromes (but less strongly expressed in B-cell responses with these negative sig- these reactive cells than in systemic mas- nals being turned off by binding of tocytosis); CD69 is expressed on cells of CD100 on T cells to CD72 on B cells 80% of cases of low grade B-lineage lym- CD72 is expressed on lymphoblasts in phoproliferative disorders (non-Hodgkin’s many cases of B-lineage acute lymphoblas- lymphoma and chronic lymphocytic tic leukaemia; co-expressed with its ligand, leukaemia) and 53% of high grade CD5, on chronic lymphocytic leukaemia non-Hodgkin’s lymphoma; expressed cells; strongly expressed on hairy cells on lymphoma cells of nasal-type NK cell CD73 a glycosylphosphatidylinositol (GPI)- lymphoma and sometime on cells of anchored protein, ecto 5′ nucleotidase, aggressive NK-cell leukaemia/lymphoma expressed on subsets of B and T cells, fol- but not those of blastic NK cell lym- licular dendritic cells, epithelial cells and phoma; overexpressed on the mast cells endothelial cells; a costimulatory molecule of indolent systemic mastocytosis for T cells; catalyses dephosphorylation of CD70 a member of the tumour necrosis purine and pyrimidine ribo- and deoxyribo- factor receptor family, ligand for CD27; nucleoside monophosphates to nucleo- the interaction of CD70 with its ligand is sides: the preferred substrate is AMP probably functionally important early CD73 is expressed on some B lym- after antigenic stimulation; expressed on phoblasts but not the most immature 10% of peripheral blood B cells and B CD74 invariant (γ) chain of the MHC cells in about 10% of germinal centres; class II complex, expressed on B cells but expressed on activated B cells and T cells not B-cell precursors, activated T cells, CD70 is expressed more often on neo- monocytes, macrophages, activated endo- plastic than on normal B cells, being thelial and activated epithelial cells expressed in about a third of cases of fol- CD75 carbohydrate determinants—non- licular lymphoma, about three-quarters sialylated/masked lactosamine epitopes of cases of large B-cell lymphoma and CD75s alpha-2,6-sialylated lactosamines in some cases of chronic lymphocytic (formerly CDw75 and CDw76); CDw75 leukaemia; expressed by Reed–Sternberg is a CD22 ligand; expressed on circulating HAE-C 01/13/2005 05:10PM Page 56

56 CDw76

B cells and germinal centre B cells of sec- of cases of lymphoplasmacytoid lym- ondary follicles but not B-cell precursors, phoma and a quarter of cases of hairy a small subset of T cells, erythrocytes and cell leukaemia; the lack of expression in some epithelial cells; expressed on B cells chronic lymphocytic leukaemia is useful including mantle zone B cells of sec- in helping to differentiate this condition ondary follicles, a subset of T cells and from non-Hodgkin’s lymphoma; ex- subsets of endothelial and epithelial cells pressed on the blast cells of some cases CD75s is expressed on immature B of acute lymphoblastic leukaemia lymphoblasts and cells of mature B- CD80 ligand of CD28 and CD152; co- lineage neoplasms regulator, with CD86, of T-cell activa- CDw76 a deleted CD designation (see tion; engagement of the T-cell receptor CD75s) without co-stimulation may lead to anergy CD77 a carbohydrate, Pk blood group rather than clonal expansion; expressed antigen, expressed on germinal centre B on T cells, activated B cells and some cells; in endothelial cells, CD77 functions dendritic cells; expressed weakly on as a receptor for verotoxin with resultant immature dendritic cells, such as those apoptosis of the cells in skin and other peripheral tissues, but CD77 is expressed by the cells of expressed strongly on mature dendritic Burkitt’s lymphoma and post-transplant cells in lymph nodes; expressed in the lymphoproliferative disorder; weakly majority of cases of Langerhans cell expressed on the cells of follicular centre histiocytosis cell lymphoma; expressed by cells of a CD81 a tetraspanin; part of a large signal minority of patients with multiple transduction complex, together with myeloma but in a majority of patients CD19 and CD21; broadly expressed on with plasma cell leukaemia haemopoietic cells but not on erythro- CDw78 a deleted CD designation cytes, platelets or neutrophils; expressed CD79a part of the immunoglobulin- on lymphocytes, endothelial cells, epi- associated heterodimeric B-cell antigen thelial cells and hepatocytes; on lympho- receptor complex; expressed on B cells cytes and hepatocytes is a receptor for the and their precursors, and on plasma hepatitis C virus cells; a useful ‘pan-B’ marker applicable CD82 Kangai 1, a member of the in immunocytochemistry and immuno- transmembrane 4 or tetraspanin super- histochemistry—monoclonal antibodies family of proteins, which functions in available detect an intracellular epitope signal transduction; almost ubiquitous CD79a is expressed on blasts cells of tissue expression; strongly expressed B-lineage acute lymphoblastic leukaemia on early haemopoietic progenitor cells; and on mature B-lineage leukaemias and moderately expressed on neutrophils and lymphomas; expressed on neoplastic cells monocytes but expressed weakly on only in nodular lymphocyte predominant about a third of peripheral blood lym- Hodgkin’s disease and expressed, more phocytes (T and B cells); a tumour metas- weakly on the neoplastic cells of a sig- tasis suppressor gene whose transcription niﬁcant minority of cases of classical is down regulated during the tumour pro- Hodgkin’s disease gression of several human adenocarcino- CD79b part of the B-cell antigen receptor mas (prostate, pancreas and breast); the complex; crucial for the correct intra- enhancer of the CD82 gene is positively cellular assembly and transport of the regulated by p53 and loss of p53 function complex; expressed on mature B cells and during tumour progression is associated late B-cell precursors (pre-B cell) with a loss of CD82 expression CD79b is expressed on most neo- CD82 is expressed in chronic lympho- plasms of mature B cells but weakly or cytic leukaemia, acute myeloid leukaemia not at all on the cells of chronic lympho- and blast crisis of chronic myeloid cytic leukaemia and in only about a half leukaemia HAE-C 01/13/2005 05:10PM Page 57

CD92 57

CD83 a transmembrane protein, which is inositol (GPI)-anchored protein, receptor expressed weakly on activated B cells and for urokinase and pro-urokinase and also activated T cells; expressed on interdig- for vitronectin; expressed on activated T itating dendritic cells and Langerhans cells, NK cells, monocytes, neutrophils, cells; may not be expressed on circulating platelets and many non-haemopoietic or bone marrow dendritic cells but is cells; has a possible role in the migration up-regulated on culture of circulating of leucocytes into tissues dendritic cells; usually expressed weakly CD88 a cell surface glycoprotein, C5a or not at all in Langerhans cell histiocyto- receptor, expressed on neutrophils and sis; expressed on activated neutrophils monocytes and has a role in their activa- CD84 a cell surface glycoprotein, expres- tion; sometimes expressed on basophils sed on mature B cells, thymocytes, a sub- but not on mast cells (with the excep- set of T cells, monocytes, macrophages tion of skin mast cells); expressed on and platelets; a receptor for the product smooth muscle cells, pulmonary epithe- of the SAP gene lial and endothelial cells and alveolar CD85 Leukocyte Immunoglobulin-like macrophages Receptor 1, LIR1; expressed on circulat- CD89 Fcα receptor, expressed on myeloid ing B cells, a minority of circulating T cells from the promyelocyte to the neu- cells and a subpopulation of circulating trophil stage, promonocytes, monocytes, NK cells; expressed on monocytes and splenic and alveolar macrophages and macrophages; strongly expressed on plasma activated eosinophils; induces phago- cells, hairy cells, mantle zone B cells and cytosis, the respiratory burst, bacterial germinal centre cells killing and degranulation; eosinophils of CD86 a cell surface protein, expressed atopic individuals show up-regulation of weakly on immature dendritic cells, such CD89 as those in skin (Langerhans cells) and CD90 Thy-1, a glycosylphosphatidylinosi- other peripheral tissues, but expressed tol (GPI)-anchored glycoprotein expressed strongly on mature dendritic cells in on lymphocytes and co-expressed with lymph nodes, e.g. interdigitating retic- CD34 on a proportion of haemopoietic ulum cells; usually expressed weakly or stem cells and prothymocytes; also ex- not at all on the cells of Langerhans cell pressed on neurones and in secreted form histiocytosis; expressed on monocytes, by neuronal accessory cells; following activated B cells, memory B cells and ger- autologous stem cell transplantation, the minal centre B cells; a ligand of CD28, number of CD34+CD90+ cells infused CD80 and CD152; co-regulator, with correlates with durability of engraftment CD80, of T-cell activation; plays a critical Expressed on the leukaemic cells in 5% role in induction and regulation of the of patients with acute myeloid or acute immune response lymphoblastic leukaemia α CD86 is expressed by Hodgkin’s cells CD91 2 macroglobulin receptor, also and Reed–Sternberg cells; expressed on known as low density lipoprotein receptor- some acute myeloid leukaemia myelo- related protein and heat shock protein blasts and has been found to correlate receptor; expressed on monocytes and with worse prognosis; is more often macrophages, including Kupffer cells expressed in M4 and M5 categories of and alveolar macrophages, neurones, acute myeloid leukaemia but not with astrocytes, smooth muscle cells, testicular sufﬁcient speciﬁcity for this to be diagno- Leydig cells and ovarian granulosa cells; stically useful; expressed on neoplastic binds protease–inhibitor complexes such α cells in about half of patient with multiple as protease– 2 macroglobulin complexes myeloma, expression correlating with a and processes and presents heat shock worse prognosis proteins CD87 plasminogen activator receptor CD92 an antigen expressed on neutrophils, uPAR, u-PAR, a glycosylphosphatidyl- monocytes, platelets and endothelium HAE-C 01/13/2005 05:10PM Page 58

58 CDw93

CDw93 expressed on neutrophils, mono- lymphoma and extra-nodal B-lineage dif- cytes and endothelial cells fuse large cell lymphoma; not expressed CD94 Killer cell Lectin-like Receptor, on chronic lymphocytic leukaemia cells subfamily D, member 1, KLRD1; an and this may contribute to the prolonged MHC Class I-specific NK receptor survival of chronic lymphocytic leuk- molecule, expressed on mature NK cells aemia cells; not expressed in acute lym- but not pre-NK cells or immature NK phoblastic leukaemia and expressed in cells; binding of cells expressing CD94 to only a half of cases of diffuse large cell cells expressing MHC Class I alleles leads lymphoma and Burkitt’s lymphoma; Fas to inhibition of cytotoxicity whereas is expressed on Reed–Sternberg cells of binding to virus-infected cells failing to most cases of Hodgkin’s disease; Fas is express MHC Class I permits cytotoxic- often overexpressed in the myelodysplastic ity; expressed on a subset of T cells; syndromes and Fas ligand may be inap- expressed on cells of nasal T/NK lym- propriately expressed on CD34+ stem phoma, aggressive NK-cell leukaemia cells so that Fas-Fas ligand interactions lymphoma and a minority of extranodal contribute to increased apoptosis cytotoxic T-cell lymphomas but not cells Fas ligand is expressed on activated of blastic NK-cell leukaemia/lymphoma lymphocytes, monocytes, neutrophils and CD95 Fas/APO-1, a transmembrane thymocytes but not on normal CD34+ protein belonging to the TNF family stem cells. Fas ligand is expressed in the that mediates programmed cell death anterior chamber of the eye so that lym- (apoptosis) when trimerized by cross- phocytes entering the anterior chamber linking to Fas ligand; cross linking leads bind to Fas ligand and undergo apoptosis. to activation of caspases, a family of pro- Fas ligand is upregulated on macrophages teases that mediate apoptotic cell death; by HIV infection so that lymphocytes expressed on activated (non-cytotoxic) that come in contact with macrophages T and B lymphocytes; responsible for undergo apoptosis eliminating autoreactive T cells during Expression of Fas ligand is increased ontogenesis and for maintaining lym- in chronic lymphocytic leukaemia/small phocyte homeostasis; inherited Fas muta- lymphocytic lymphoma and marginal tions are responsible for an autoimmune zone lymphoma; fas ligand is expressed lymphoproliferative syndrome; CD95/Fas on myeloma cells and may induce apop- is expressed on thymic medullary epithelial tosis in T cells; Fas ligand is expressed on cells; Fas is expressed on early erythro- Reed–Sternberg cells of about a third of blasts whereas Fas ligand is expressed cases of Hodgkin’s disease but although on late erythroblasts, permitting negative Fas may be coexpressed apoptosis does feedback control which can be abrogated not appear to occur by high concentrations of erythropoietin; CD96 a protein, a member of the immuno- Fas is expressed on dendritic cells; ex- globulin gene superfamily expressed on pressed on reactive plasma cells and activated T cells and activated NK cells, normal tonsillar plasma cells so that peaking 6 to 9 days after the activating they are susceptible to apoptosis but not stimulus expressed on normal bone marrow CD97 a glycoprotein expressed strongly plasma cells; an HIV protein, type 1 nef, by monocytes and macrophages and less upregulates Fas on CD4+ lymphocytes, strongly by neutrophils; not expressed by leading to apoptosis and T-cell depletion; resting lymphocytes but upregulated on the Fas/FasL pathway may specifically activation; a member of the EGF-TM7 kill virally infected or transformed cells family of cell surface proteins; alternative The Fas gene is mutated in a signific- exon splicing leads to several isoforms ant proportion (about 10%) of cases of which have varying numbers of extracel- multiple myeloma and non-Hodgkin’s lular EGF repeats; related to the secretin lymphoma, particularly MALT-type and calcitonin receptors; interacts with HAE-C 01/13/2005 05:10PM Page 59

CD105 59

the human complement regulator, CD55 interaction with CD72 on B lymphocytes —the physiological role of this is not is essential for production of T-cell known dependent antibodies CD98 a protein, Solute Carrier family 3, CD101 a protein, Immunoglobulin member 2, SLC3A2; an L-phenylalanine Superfamily, member 2, IGSF2; ex- transporter; expressed on activated pressed on monocytes, neutrophils, cuta- monocytes, T lymphocytes and B lym- neous dendritic cells and activated T cells phocytes CD101 is a marker of Langerhans cell Expressed on neoplastic cells in most histiocytosis cells patients with multiple myeloma—failure CD102 Intercellular adhesion molecule 2 of expression appears to correlate with (ICAM-2); an adhesion molecule that is β resistance to melphalan therapy the ligand of the 2 integrin CD11a/ CD99 MIC2, a transmembrane sialogly- CD18; expressed on endothelial cells, coprotein encoded by the first identified platelets, monocytes and some lympho- Y chromosomal structural gene; located cytes; acts as a costimulatory molecule in on the pseudo-autosomal region of the the immune response and has a role in Y chromosome; the corresponding X lymphocyte recirculation chromosomal gene, MIC2X escapes X CD103 human mucosal lymphocyte inactivation; broadly expressed on haemo- antigen 1, alpha subunit; a cell surface poietic and lymphoid cells (including thy- antigen, αE integrin, which forms a het- mocytes, T cells and B cells); involved in erodimer with β7 integrin; expressed on cell-cell adhesion during haemopoietic mucosa-associated T lymphocytes, other cell differentiation and apoptosis of intra-epithelial lymphocytes and a small immature thymocytes; expressed on a subset of peripheral blood lymphocytes subset of pancreatic islet cells (2–6%); expressed on monocytes CD99 is not expressed on Reed– CD103 is expressed by hairy cells and Sternberg or Hodgkin’s cells; expressed in adult T-cell leukaemia/lymphoma and on the blast cells in the majority of cases enteropathy-associated T-cell non- of acute myeloid leukaemia and acute Hodgkin’s lymphoma lymphoblastic leukaemia and on cells CD104 a cell surface antigen, β4 integrin α β of Ewing’s tumour, primitive neuroecto- chain, expressed as 6/ 4 integrin in ker- dermal tumours and peripheral neuro- atinocytes; expressed on Schwann cells epitheliomas; useful in the diagnosis of and some tumour cells; mutations in the atypical fibroxanthoma; expressed more β4 integrin gene have been found in chil- weakly in Burkitt-type acute lympho- dren with the non-lethal form of junc- blastic leukaemia than precursor-B acute tional epidermolysis bullosa and pyloric lymphoblastic leukaemia; Epstein–Barr atresia; these cases have all been com- virus LMP down-regulates CD99 expres- pound heterozygotes for a nonsense and sion on B cells, possibly contributing a mis-sense mutation; compound het- to viral oncogenesis in EBV-positive erozygosity for two nonsense mutations Hodgkin’s disease or homozygosity for a single nonsense α β CD100 a transmembrane semaphorin allele results in stillbirth; 6 4 integrin is expressed on late haemopoietic cells, T also expressed on thymic epithelial cells, cells, germinal centre B cells, NK cells, permitting the adhesion of thymocytes neutrophils and monocytes; more strongly CD105 endoglin, a homodimeric mem- expressed on activated T cells and B brane glycoprotein that is a high-affinity cells; has a role in cell adhesion; ligand receptor for transforming growth factor of CD45; induces B-cell aggregation and β1 and β3; expressed on endothelial cells, down-regulates B-cell expression of CD23; activated monocytes, macrophages, can be cleaved from the cell surface to early B-cell precursors, stromal cells of give a functional soluble semaphorin, the bone marrow, erythroid precursors which inhibits monocyte migration; and some haemopoietic stem cells; in the HAE-C 01/13/2005 05:10PM Page 60

60 CD106

embryo, CD105 expression is essential endothelium and neutrophils; mediates for myeloid and erythroid differentia- mononuclear cell adhesion to vascular tion; encoded by the target gene that endothelium is mutated in hereditary haemorrhagic CD108 a protein expressed on red cells telangiectasia and lymphoblasts and more weakly on CD106 a cell surface antigen, VCAM-1, lymphocytes; expressed on erythrocytes; Vascular Cell Adhesion Molecule; a the JMH blood group antigen member of the immunoglobulin gene CD109 a glycosylphosphatidylinositol α β superfamily; expressed on activated (GPI)-linked glycoprotein, v 3 integrin, endothelium, some tissue macrophages, expressed on activated T cells, platelets, dendritic cells and bone marrow ﬁbrob- megakaryocytes, endothelial cells and lasts; expression of VCAM-1 is increased haemopoietic stem cells by IL1α, TNFα, IL4 and lipopolysaccha- CD110 thrombopoietin receptor, a ride; upregulated by exposure to vero- member of the cytokine receptor toxin, promoting neutrophil adhesion to superfamily, expressed on a stem cell endothelium; mediates the adhesion of subset, megakaryocytes and, weakly, on monocytes, lymphocytes and eosinophils platelets; encoded by the MPL gene at to activated endothelial cells; to a lesser 1p34; homologue of the murine viral extent, mediates adhesion of neutrophils, oncogene, v-mpl (Myeloproliferative probably by means of binding to an Leukaemia Virus); mutations in MPL are α 4 integrin; expression of VCAM-1 is found in patients with congenital amega- increased when the erythrocytes of sickle karyocytic thrombocytopenia; expressed cell anaemia (SS) adhere to endothelium, by common myeloid but not common which further increases adhesion of SS lymphoid progenitor cells α β reticulocytes, expressing 4 1 integrin, to CD111 a protein, nectin-1/Poliovirus activated endothelium; expressed at a Receptor-Like, PVRL1; a component of low level on bone marrow stromal cells, adherens junctions; expressed on a stem expression being upregulated by TNFα, cell subset, macrophages, neutrophils IL1, IL4 and IL13; administration of and neurones; an adhesion molecule G-CSF leads to release of neutrophil and receptor for Herpes simplex viruses; proteases in the bone marrow with two isoforms are known with differing cleavage of VCAM-1 on bone marrow intracellular domains; mutations in the stromal cells, which may lead to release PVRL1 gene have been found in kindreds of haemopoietic stem cells with the cleft lip/palate–ectodermal dys- Soluble VCAM-1 is increased in chronic plasia syndrome (CLPED1) lymphocytic leukaemia and, although it CD112 a protein, nectin-2/PRR2, ex- is not expressed on the leukaemic cells, pressed on neurones, endothelial cells epi- correlates with tumour burden; soluble thelial cells, monocytes, megakaryocytes, VCAM-1 is increased in acute leukaemia, neutrophils and a stem cell subset; a Hodgkin’s disease and advanced-stage component of adherens junctions; two non-Hodgkin’s lymphoma; increased isoforms are known with differing intra- serum levels in non-Hodgkin’s lymphoma cellular domains correlate with a worse prognosis CD113 an unassigned CD number CD107a Lysosomal Membrane Protein CD114 the receptor for granulocyte colony- 1 (LAMP-1), expressed by degranulated stimulating factor (G-CSFR); CSF3R; platelets, activated T cells, neutrophils expressed at all stages of neutrophil dif- and activated endothelium; mediates ferentiation and on monocytes, platelets mononuclear cell adhesion to vascular and endothelial cells; has a major role in endothelium regulation of proliferation and differ- CD107b Lysosomal Membrane Protein entiation of cells of neutrophil lineage; 2 (LAMP-2), expressed on activated mutations of this gene are responsible for platelets and weakly on activated some cases of severe congenital neutro- HAE-C 01/13/2005 05:10PM Page 61

CD122 61

penia; binding to G-CSF down-regulates with megakaryoblasts as well as myelo- CD114 and induces gelatinase B release blasts expressing the antigen; expressed CD115 a glycoprotein, M-CSF receptor in systemic mastocytosis; expressed on (Macrophage Colony Stimulating Factor some myeloma cells but not on the cells of Receptor) or CSF1, a receptor tyrosine plasma cell leukaemia; rarely expressed in kinase which is encoded by the FMS T-lineage acute lymphoblastic leukaemia (CSF1R) gene; expressed on monocytes CD118 interferon α.β receptor; a broadly and macrophages, placental cells and expressed protein some choriocarcinoma cells; CDw119 an interferon receptor, IFNγR1; CD115 is expressed by some acute expressed on monocytes, macrophages, B myeloid leukaemia cells; mis-sense point cells and endothelium; a mutation in the mutations in codons 301 or 969 of the gene encoding this protein causes suscepti- FMS gene have been found in chronic bility to atypical mycobacterial infections myelomonocytic leukaemia and M4 CD120a a receptor for tumour necrosis acute myeloid leukaemia; in one series, factor α; Tumor Necrosis Factor Receptor 1/51 haematologically normal subjects subfamily, member 1A, TNFRI; expressed were shown to have the mutation in on haemopoietic and non-haemopoietic codon 969; this may represent a marker cells, most strongly on epithelial cells; of predisposition to myeloid malignancy mutations in the TNFR1 gene have been CD116 the α chain of the Granulocyte- linked with familial autosomal dominant Macrophage Colony Stimulating Factor periodic fever syndromes Receptor (GM-CSFR), the β chain being CD120b a receptor for tumour necro- CDw131; expressed on monocytes, macro- sis factor α; Tumour Necrosis Factor phages, neutrophils, eosinophils and Receptor subfamily, member 1B, TNFRII; dendritic cells; sometimes expressed on expressed on haemopoietic and non- basophils but not on mast cells; the gene haemopoietic cells, most strongly on for this protein is located in the pseu- myeloid cells, activated T cells and doautosomal region of the short arm of activated B cells; polymorphisms in the the X and Y chromosomes, distal to the TNFR2 gene have been linked with CD99 locus familial combined hyperlipidaemia CD117 c-KIT, the receptor for stem CD121a a receptor for IL1α and IL1β; cell factor (SCF-R), a receptor tyrosine IL1R type 1, IL1RI, expressed on T cells kinase; expressed on haemopoietic pre- CD121b a receptor for IL1, IL1R type II, cursors, myeloblasts, primitive erythroid IL1RII; possibly inhibits IL1 activity by cells, mast cells, a subset of NK cells binding IL1 that would otherwise bind to and a range of non-haemopoietic cells IL1RI; expressed on B cells, monocytes including the interstitial cells of Cajal and macrophages Auerbach’s plexus, melanocytes, testis, CD122 Interleukin 2 Receptor beta vascular endothelium, stromal fibrob- chain (IL2Rβ); together with CD25 and lasts, astrocytes, renal tubules, breast CD132, forms a high affinity IL2R which glandular epithelium and sweat glands; is expressed on T cells, B cells, NK cells, not expressed on basophils; expressed monocytes and macrophages; CD122 is on early B lymphoid cells and immature also a subunit of IL15R which is ex- thymic T cells; point mutations in c-KIT pressed on activated monocytes and on have been found in familial piebaldism various non-haemopoietic cells; not and megacolon and in gastrointestinal expressed by basophils or mast cells; stromal tumours which are thought to be targeted disruption of the murine gene derived from interstitial cells of Cajal, leads to uncontrolled B-cell prolifera- express CD117, and respond to therapy tion with hypergammaglobulinaemia and with imanitib mesylate, a c-KIT inhibitor an autoimmune haemolytic anaemia; CD117 is expressed by the blast cells of KIT-ligand (SCF) and flt-3 ligand induce most cases of acute myeloid leukaemia expression of CD122 on CD34bright haemo- HAE-C 01/13/2005 05:10PM Page 62

62 CD123

poietic progenitor cells which can then association with the signal transducing be induced to differentiate to NK cells by molecule, CD130 the action of IL15 CD127 Interleukin 7 Receptor alpha chain CD123 Interleukin 3 Receptor alpha (IL7Rα), combines with the β chain, chain (IL3Rα); the α subunit is ligand CD132, to form a high affinity receptor; specific whereas the β subunit, CD133, is expressed on most T cells, being down- shared with GM-CSFR and IL5R; the regulated on T-cell activation; expressed gene is located in the pseudoautosomal on B-cell precursors and monocytes region at the end of the short arm of the X CDw128a Interleukin 8 Receptor Alpha and Y chromosomes expressed on haemo- (IL8RA, IL8Rα); a high affinity receptor poietic stem cells, granulocytes, mono- for IL8 cytes and megakaryocytes; expressed on CDw128b Interleukin 8 Receptor Beta basophils but not mast cells; expressed on (IL8RB, IL8Rβ), a low affinity receptor lymphoid dendritic cells for IL8 Expressed on blast cells of the major- CD130 a widely expressed molecule that ity of patients with acute myeloid associates with CD126 after CD126 has leukaemia but not expressed on normal bound to its ligand, IL6, and similarly CD34+CD38– bone marrow stem cells associates with the IL11R after it has CD124 Interleukin 4 Receptor alpha bound IL11; receptor for oncostatin M; chain (IL4Rα), combines with the IL4Rβ part of the signalling system after cells chain, CD132, to form the receptor; have bound IL6 or IL11; expressed on expressed on T cells, B cells and haemo- activated B cells and plasma cells poietic cells; also contributes the α chain CD130 is expressed on plasma cells in of IL13R, combining with IL13Rβ chain about 40% of patients with multiple to form the receptor; susceptibility to myeloma at diagnosis and a similar atopy and increased levels of expression proportion of cases of monoclonal gam- of CD23 have been associated with a mopathy of undetermined significance; mis-sense mutation in codon 576 of the may have a role in maintaining growth IL4Rα gene; several mis-sense mutations and survival of neoplastic plasma cells; at codon 50 have been associated with expressed on about 90% of cases of susceptibility to asthma, atopy and elev- relapsed multiple myeloma and in about ated IgE levels half of these is co-expressed with CD126 CDw125 Interleukin 5 Receptor alpha CDw131 the β subunit of GM-CSFR chain (IL5Rα), which combines with (combining with CD116), of the IL3R CDw131, the β chain, to form a high affinity (combining with CD123) and of the IL5 receptor; expressed on eosinophils, IL5R (combining with CDw125); ex- activated B cells and basophils; soluble pressed on most myeloid cells isoforms of the IL5R α chain occur CD132 the common γ chain of a number normally because of alternative splicing of cytokine receptors: CD126 Interleukin 6 Receptor alpha • Combining with CD122 and CD25 to chain (IL6Rα); expressed on T cells, activ- form the high affinity IL2R ated B cells and monocytes; in reactive • Combining with CD124 to form the conditions, expressed on plasmablasts high affinity IL4R and immature plasma cells but not • Combining with CD127 to form the mature plasma cells high affinity IL7R CD126 is expressed on plasma cells in • Combining with IL15Rα and CD122 about 50% of patients with monoclonal to form the IL15R gammopathy of undetermined signific- • Also part of the receptor for IL9 ance and 90% of patients with multiple Expressed on T cells, B cells, NK cells, myeloma; may have a role in maintaining monocytes, macrophages and neutrophils; growth and survival of neoplastic plasma mutation leads to sex-linked severe cells since IL6 binds to CD126 triggering combined immunodeficiency HAE-C 01/13/2005 05:10PM Page 63

CD139 63

CD133 a protein, AC133, expressed on ciliated epithelial cells; has a role in stem cell/progenitor cell subsets which induction of macrophage migration can give rise to endothelial cells as well CDw137 a protein, a member of the as haemopoietic cells tumour necrosis receptor family, encoded Expressed on blast cells of the majority by a gene at 1p36; expressed by activated of patients with acute myeloid leukaemia T and B cells and monocytes; a costimu- and acute lymphoblastic leukaemia but latory molecule in T-cell proliferation; B not expressed on normal CD34+CD38– cells, activated T cells and monocytes bone marrow stem cells. In patients with express CD137 ligand; soluble CD137 acute myeloid leukaemia, expression cor- stimulates proliferation of peripheral relates with other markers of immatur- blood monocytes; expressed by endothe- ity, with M0 subtype being most often lial cells and vascular smooth muscle positive and with M3/M3 subtype not cells in abnormal tissues, particularly showing expression. Expression is more malignant tumours, but not in normal frequent in B-lineage than T-lineage tissues acute lymphoblastic leukaemia and is CD138 a heavily glycosylated transmem- characteristic of acute lymphoblastic brane molecule (heparan sulphate pro- leukaemia with t(4;11) and rearrange- teoglycan), an adhesion molecule, LFA-3 ment of the MLL gene or Syndecan-1, that mediates the interac- CD134 a protein, OX40, a member of tion between cells and the extracellular the TNF receptor superfamily; expressed environment—mediating adhesion and on activated lymphocytes; an early acti- regulating growth factor activities; ex- vation marker on germinal centre T cells; pressed on post-germinal centre B cells interacts with its ligand expressed on but not germinal centre B cells; expressed antigen-presenting cells; interaction of on epithelial cells; expressed by plasma CD134 with its ligand has an important cells including early plasma cells but role in acute graft-versus-host disease not expressed by reactive plasmablasts and numbers of CD134+ T lymphocytes CD138 is expressed by multiple correlate with chronic-graft-versus host myeloma cells and in some lympho- disease mas including lymphoplasmacytoid CD134 is expressed in many T-cell lymphoma; serum CD138 is of prog- lymphomas including angioimmunoblas- nostic signiﬁcance in multiple myeloma; tic, angiocentric and histiocyte-rich T-cell expressed on neoplastic cells of some lymphoma but not in anaplastic large cell cases of classical Hodgkin’s disease but lymphoma not on the cells of nodular lymphocyte CD135 ﬂt3, a receptor tyrosine kinase, predominant Hodgkin’s disease; cells a growth factor receptor that binds to of chronic lymphocytic leukaemia show FLT3 ligand; expressed on multipotent weak or moderate cytoplasmic and stem cells, myelomonocytic precursors membrane expression; expressed on HIV- and early B-cell progenitors; has a role in associated primary effusion lymphoma; the proliferation and differentiation of CD138-coated beads can be used for haemopoietic progenitors purifying myeloma cells; has been used, CD135 is expressed on blast cells in together with pan-B monoclonal anti- acute lymphoblastic leukaemia, acute bodies, for purging peripheral blood stem myeloid leukaemia and the blast crisis of cell harvests for autologous transplanta- chronic granulocytic leukaemia; acquired tion in multiple myeloma mutations in FLT3 have been found in CD139 a protein, expressed on B cells, acute myeloid leukaemia and indicate a monocytes, neutrophils and follicular poor prognosis dendritic cells CDw136 a receptor tyrosine kinase, CD139 is expressed on cells of some receptor for macrophage stimulating but not all cases of chronic lymphocytic protein; expressed on macrophages and leukaemia HAE-C 01/13/2005 05:10PM Page 64

64 CD140a

CD140a Platelet-Derived Growth Factor identify and select circulating endothelial Receptor Alpha (PDGFRα), a receptor cells; a marker for melanoma, associated tyrosine kinase with tumour progression and metastasis CD140b Platelet-Derived Growth Factor CD147 a protein known as neurothelin, Receptor Beta (PDGFRβ), a receptor basigin, EMMPRIN (Exracellular Matrix tyrosine kinase; expressed on endothelial Metalloproteinase Inducer); a member of cells, smooth muscle cells, fibroblasts, the immunoglobulin gene superfamily, glial cells, chondrocytes, B and T lym- an adhesion molecule; expressed on phocytes and myeloid cells including leucocytes (neutrophils, monocytes and megakaryocytes and platelets lymphocytes) and erythrocytes and their The gene encoding CD140b, which precursors, macrophages, dendritic cells, is on chromosome 5, is often deleted in platelets and endothelial cells; possibly an the 5q– syndrome and is rearranged adhesion molecule. CD147 is upregulated in several uncommon chronic myeloid when T and B lymphocyte are activated; leukaemias (see PDGFRB) receptor for cyclophilin A (a cyclosporin CD141 a cell surface glycoprotein, throm- binding protein); anti-CD147 has some bomodulin, expressed on endothelial cells; efficacy in graft-versus-host disease the cofactor for thrombin-mediated CD148 a protein, HPTP-eta, p260 phos- expression of activated protein C; het- phatase; expressed on neutrophils, eosino- erozygosity for a mis-sense mutation in phils, monocytes, T cells, some B cells, the thrombomodulin gene has been asso- NK cells, dendritic cells, platelets and ciated with familial thrombophilia epithelial cells; expressed on memory B CD142 tissue factor; CD142 plus factor cells and on the cells of polyclonal B-cell VIIa initiates the coagulation cascade lymphocytosis, which may represent an through factors X and IX; VIIa is the expansion of memory B cells; a mem- catalytic subunit while CD142 is the regu- brane tyrosine phosphatase, which acts latory subunit; induced on monocytes as a transducing molecule but also mod- and endothelial cells by inflammatory ulates signalling, e.g. through the T-cell mediators receptor/CD3 complex CD143 Angiotensin-Converting Enzyme CDw149 an antigen that has been redes- (ACE); expressed on some endothelial ignated CD47R cells, and some epithelial and neuronal CD150 a protein, Signalling Lymphocyte cells, monocytes, activated macrophages, Activation Molecule (SLAM), IPO-3; a small number of T cells and sperm- a member of the immunoglobulin gene atozoa; metabolizes angiotensin II and superfamily; expressed on thymocytes, B bradykinin; increased expression of CD143 cells, some T cells and dendritic cells; a on endothelial cells may be relevant to the costimulatory molecule on B cells and development of atherosclerosis; has a role dendritic cells; a mutation in the SAP in binding spermatazoa to the ovum (SLAM-Associated Protein) gene, which CD144 VE-cadherin, a protein expressed encodes a ligand of SLAM, is the cause of on endothelium that mediates homotypic X-linked lymphoproliferative disease adhesion CD151 Platelet-Endothelial Tetraspan CDw145 a protein that is expressed Antigen 3 (PETA3), a member of the constitutively on endothelial cells and transmembrane 4 or tetraspanin super- some bone marrow stromal cells family of proteins, expressed on endo- CD146 a protein, a member of the thelial cells, platelets, monocytes and immunoglobulin gene superfamily, also immature haemopoietic cells known as MUC18 and S-endo; expressed CD152 a protein, Cytotoxic T associ- on endothelium and activated T cells; a ated Lymphocyte Antigen 4 (CTLA4), component of the endothelial junction, expressed on activated T cells; shows involved in cell–cell cohesion; mono- partial homology with CD28; like CD28, clonal CD146 antibodies can be used to binds CD80 and CD86 and is probably HAE-C 01/13/2005 05:10PM Page 65

CD158b 65

mainly a negative regulator of T-cell act- soluble CD154 is increased in chronic ivation; mis-sense mutations in codon 17 lymphocytic leukaemia and could pro- have been reported to be associated with mote cell survival; strongly expressed on autoimmune endocrinopathies; a CD152- hairy cells; transduction of the CD154 immunoglobulin fusion protein has been gene into autologous lymphoid cells has used experimentally in the treatment of been used experimentally in immunother- psoriasis apy of chronic lymphocytic leukaemia CD153 a cytokine, CD30 ligand or CD155 a protein, polio virus receptor CD30L, shows homology with tumour (PVR), a member of the immunoglobulin necrosis factor; expressed on neutro- superfamily; expressed on B cells, mono- phils, activated T cells, monocytes and cytes and neural cells macrophages CD156a a protein, previously designated CD153 (CD30 ligand) is expressed, CD156, also known as ADAM8, MS2 together with CD30, on the neoplastic (mouse homologue); a zinc metallo- cells of cutaneous anaplastic large cell protease expressed on neutrophils and lymphoma, with overexpression probably monocytes; upregulated by retinoic acid contributing to spontaneous regression CD156b a protein, Tumour necrosis factor- CD154 a protein, CD40 ligand or CD40L, Alpha (TNFα)-Converting Enzyme, expressed on activated CD4+ lympho- TACE, also known as ADAM 17; cytes, expression being essential for broadly expressed adhesion structures normal signalling to B cells, particularly CD157 a glycosylphosphatidylinositol for isotype switching; mutations in the (GPI)-anchored protein with structural CD154 gene are responsible for the similarities to CD38, Bone marrow X-linked immunodeficiency syndrome, Stromal cell antigen 1 (BST-1), a cyclic the hyperIgM syndrome; expressed on ADP-ribose hydrolase and ADP ribosyl monocytes, macrophages, eosinophils, cyclase; expressed on myeloid precursors, basophils, NK cells, platelets, dendritic neutrophils, monocytes, mast cells, cells, epithelial cells, endothelial cells and macrophages, follicular dendritic cells, fibroblasts; on platelet activation, CD154 endothelial cells, bone marrow stromal moves to the surface membrane and has cells, gut epithelial cells, mesothelial cells, the potential to interact with CD40 on α and β cells of pancreas; over-expressed endothelial cells, leading to an inflammat- in bone marrow stromal cells and prob- ory reaction, which is limited by bind- ably synovial cells in rheumatoid arthritis; ing of CD154 to co-expressed platelet interaction of CD157+ nurse-like cells CD40; CD154 stimulates myelopoiesis, with B cells may underlie the polyclonal particularly megakaryocytopoiesis by B-cell activation in rheumatoid arthritis; up-regulating flt3-ligand and throm- soluble CD157 correlates with disease bopoietin; CD154 expression on CD4+ activity in rheumatoid arthritis lymphocytes is increased in HIV infection CD158a two proteins, p58.1 and p50.1, and may contribute to hyperimmuno- MHC class I-specific (HLA-C-specific) globulinaemia; CD154 in the supernatant NK receptors; members of the KIR may cause febrile reactions following (Killer Inhibitory Receptor) family and platelet transfusion; monoclonal anti- immunoglobulin gene super-family; bodies to CD154 have been used in the expressed on a NK subset and rare T therapy of autoimmune thrombocy- cells; p58.1 is inhibitory and p50.1 is topenic purpura and to facilitate allo- stimulatory; following engagement of genic engraftment CD158a, inhibition of NK cell activity is CD154 is co-expressed with CD40 seen on some non-Hodgkin’s cells so that CD158b two proteins, p58.2 and p50.2, an autocrine loop may occur; it is co- MHC class I-specific NK (HLA-C- expressed with CD40 on cells of some specific) receptors; members of KIR cases of chronic lymphocytic leukaemia; family and immunoglobulin gene super- HAE-C 01/13/2005 05:10PM Page 66

66 CD159a

family; expressed on a NK subset and tein of 24 kilodaltons), a transmembrane rare T cells; T cells that express CD158b homodimer, expressed on haemopoietic are CD3+, CD8+, TCRα/β+ and CD56+ progenitors, bone marrow stromal cells, CD159a a protein, p70, NKG2A/KIR; endothelial cells and some epithelial cells; a member of the KIR family and the participates in the binding of CD34+ cells immunoglobulin gene superfamily, ex- to bone marrow stroma and inhibits the pressed on NK cells recruitment of such cells into cell cycle; CD160 a protein, BY55, expressed on expressed on both CD34+ stem cells and T-cell subset and NK cell subset; a co- on more primitive CD34− stem cells stimulatory molecule CD165 an adhesion molecule, GP/37/ CD161 a lectin, NKRP-1, expressed on AD2, expressed on a subset of T lympho- most NK cells, both mature and imma- cytes, immature thymocytes, monocytes ture, pre-NK cells, a subset of T cells and and most platelets and expressed at a low a subset of thymocytes level on most thymocytes and on thymic CD161 is expressed in aggressive and epithelium; may have a role in adhesion nasal type NK-cell leukaemia/lymphoma of thymocytes to thymic epithelium and but not blastic NK-cell leukaemia/ the adhesion of T lymphocytes to epi- lymphoma dermal keratinocytes; strongly expressed CD162 a cell surface glycoprotein, P in many T-lineage acute lymphoblastic Selectin Glycoprotein Ligand 1 (PSGL-1) leukaemias or cutaneous leucocyte antigen, a mucin- CD166 an adhesion molecule, Activated like molecule; ligand for CD42P (P Leucocyte Cell Adhesion Molecule selectin), CD62E (E selectin) and CD42L (ALCAM), also known as HCA, a mem- (L selectin) and the bacterium which ber of the immunoglobulin gene super- causes human granulocytic ehrlichiosis; family; expressed on thymic epithelial expressed on haemopoietic progenitors cells, activated T cells, monocytes, and most myeloid cells, most T cells and CD34+CD38+ haemopoietic progen- some B cells; expressed more strongly on itors and a subset of stromal cells at sites monocytes than on neutrophils; permits of haemopoiesis; mediates homophilic lymphocytes and neutrophils to roll on and heterophilic adhesion by binding to activated endothelium; binds haemopoi- its ligand, CD6; expressed on endothe- etic precursors to P selectin; inﬂuences lium of yolk sac and dorsal aorta and has binding of neutrophils to activated platelets, a crucial role in embryonic haemopoiesis polymorphic variants being implicated in and vasculoangiogenesis susceptibility to cerebrovascular disease CD167a a receptor tyrosine kinase activ- CD162 is expressed more weakly on ated by collagen, an adhesion structure, myeloblasts than mature neutrophils. Discoidin Domain Receptor (DDR1); Expression on monoblasts is similar to expressed on epithelial cells and myoblasts that on monocytes and is stronger than CD168 an adhesion structure, RHAMM; expression on myeloblasts expressed on thymocyte, T-cell subsets CD162R a protein, PEN5, expressed on NK and monocytes; there are at least three CD163 a protein, M130; a member of the splice variants; overexpressed in multiple scavenger receptor superfamily, a scav- myeloma, B-cell non-Hodgkin’s lymphoma enger receptor for haemoglobin, binding and chronic lymphocytic leukaemia to haemoglobin–haptoglobin complexes CD169 an adhesion structure, siaload- in plasma; expressed on macrophages hesin; expressed on a macrophage subset; and weakly on circulating monocytes a ligand for MUC.1 (CD227) on breast (expression being up-regulated by activa- epithelial cells tion during infection and in myelopro- CD170 an adhesion structure, Sialic acid- liferative disorders) binding Immunoglobulin-like Lectin 5 CD164 a mucin-like glycoprotein, (siglec-5); expressed on a macrophage MGC-24 (Multiglycosylated Core pro- subset and neutrophils HAE-C 01/13/2005 05:10PM Page 67

CD203c 67

CD171 an adhesion structure, L1-CAM; CD183 chemokine receptor 3, CXCR3, expressed on neurones, monocytes, a T- a chemokine receptor expressed on activ- cell subset and B cells; mutations in the ated T cells and activated NK cells; L1-CAM gene give rise to a spectrum of expressed by B-CLL cells familial X-linked recessive neurological CD184 chemokine receptor 4, CXCR4, disorders collectively termed CRASH a chemokine receptor for chemokines syndrome of the CXC family, expressed on a T- CD172a an adhesion structure, SIRP cell subset, B cells, monocytes, dendritic alpha; expressed on monocytes, a T-cell cells and endothelial cells; it is a co- subset and stem cells receptor for entry of certain T-cell CD173 a carbohydrate structure, blood tropic strains of HIV into CD4+ T cells group H, type 2; expressed on erythroid CD184 is expressed in B-lineage acute cells, a stem cell subset and platelets lymphoblastic leukaemia; high expres- CD174 a carbohydrate structure, Lewis sion predicts extramedullary organ inﬁl- y; expressed on a stem cell subset and tration in childhood acute lymphoblastic epithelial cells leukaemia CD175 a carbohydrate structure, Tn; CD195 CCR5, a chemokine receptor expressed on a stem cell subset expressed on monocytes and a T-cell CD175s a carbohydrate structure, sialyl- subset, which binds several β chemokines Tn; expressed on erythroblasts and, when expressed on macrophages, CD176 a carbohydrate structure, TF permits entry of macrophage-tropic strains (Thomas-Friedrenreich antigen); expres- of HIV; certain polymorphisms in the sed on a stem cell subset CCR5 gene confer resistance to HIV CD177 a protein, NB1, expressed on a infection; a polymorphism for the CCR5 neutrophil subset; carries epitopes of the gene is associated with reduced likelihood NB1 family of neutrophil alloantigens of asthma, reduced severity of rheuma- CD178 Fas ligand, Tumour Necrosis toid arthritis and improved survival of Factor ligand Superfamily, member 6; renal allografts (TNFSF6); expressed on activated T CDw197 CCR7, a chemokine receptor cells; mutations in the CD178 gene expressed on a T-cell subset have been identiﬁed in patients with CD200 OX2, a cell surface glycoprotein, the autoimmune lymphoproliferative syn- member of the immunoglobulin super- drome (see also CD95) family; expressed on thymocytes, B cells, CD179a a protein, VpreB, expressed on activated T cells, neurons and endothelial very early B-cell precursors, pro-B and cells; CD200 receptor is expressed on early pre-B cells where, together with myeloid cells and CD200 may inhibit CD179b, it complexes with CD79a, function of myeloid cells CD79b and µ immunoglobulin heavy CD201 Endothelial Protein C Receptor chains to form the B-cell receptor; (EPCR), expressed on an endothelial cell CD179a and CD179b are replaced, later subset; polymorphisms in the EPCR gene in B-cell ontogeny, by immunoglobulin; may be associated with late miscarriage expressed on about 0.1% of cells in and myocardial infarction normal bone marrow but on a larger CD202b Tie2 (Tek), a receptor tyrosine proportion in regenerating marrow kinase expressed on endothelial cells and CD179a is expressed in some cases stem cells; receptor for angiopoietin-1; of B-lineage acute lymphoblastic polymorphisms in the TIE2 gene are leukaemia associated with familial multiple cuta- CD179b a protein, Lambda 5, expressed neous and mucosal venous malformation on B-cell precursors (see CD179a) syndromes CD180 a protein, RP105/Bgp95, ex- CD203c phosphodiesterase 3, NPP3/ pressed on mantle and marginal zone B PDNP3, expressed on basophils and cells, monocytes and dendritic cells megakaryocytes HAE-C 01/13/2005 05:10PM Page 68

68 CD204

CD204 macrophage scavenger receptor, plasms and by the cells of ALK-positive expressed on macrophages nodal (but not cutaneous) anaplastic CD205 a protein, DEC205, expressed on large cell lymphoma dendritic cells and thymic epithelium CD228 a protein, melanotransferrin, CD206 macrophage mannose receptor, expressed on melanoma cells expressed on a dendritic cell subset, CD229 a protein, Ly9, expressed on T macrophages and monocytes cells and B cells CD207 langerin, a lectin expressed on CD230 prion protein, broadly expressed; immature Langherhans cells expressed in neurones and is thought to CD208 a protein, DC-LAMP, expressed be involved in synaptic transmission; in on interdigitating dendritic cells prion diseases, such as bovine spongi- CD209 a protein, DK-SIGN, expressed form encephalopathy and Creutzfeldt– on a dendritic cell subset Jakob disease, the normal cellular prion CDw210 1L10 receptor, expressed on T protein alters its conformation on con- cells, B cells, NK cells, monocytes and tact with infectious prion protein from macrophages another host CDw210 is expressed in chronic lym- CD231 a protein, TALLA-1/A15, found phocytic leukaemia in normal brain and skeletal muscle CD212 IL12 receptor, expressed on act- CD231 is expressed in T-cell leukaemia ivated T cells and activated NK cells and on neuroblastoma cells CD213a1 IL13 receptor alpha 1, expres- CD232 a protein, VESP receptor, a sed on B cells, monocytes, ﬁbroblasts broadly expressed molecule and endothelial cells; upregulated in CD233 a protein, band 3, expressed on bronchial smooth muscle of asthmatics erythroid cells CD213a2 IL13 receptor alpha 2, CD234 Fy (Duffy)-glycoprotein (DARC), expressed on B cells and monocytes expressed on erythroid cells CDw217 IL17 receptor, a broadly ex- CD235a a glycoprotein, glycophorin A, pressed molecule expressed on erythroid cells CD220 insulin receptor α subunit, a CD235b a glycoprotein, glycophorin B, broadly expressed molecule expressed on erythroid cells CD221 IGF1 receptor, a broadly ex- CD235ab glycophorin A/B cross-reactive pressed molecule monoclonal antibodies detecting anti- CD222 mannose-6-phosphate/IGF2 gens on erythroid cells receptor, a broadly expressed molecule CD236 glycoproteins, glycophorin C/D, CD223 a protein, LAG-3, expressed on expressed on a stem cell subset and ery- activated T cells and activated NK cells throid cells CD224 gamma-glutamyl transferase, ex- CD236R a glycoprotein, glycophorin C, pressed on leucocytes and stem cells expressed on a stem cell subset and ery- CD225 a protein, Leu13, a broadly throid cells expressed molecule CD238 a protein, Kell, expressed on a CD226 a protein, Dnax Accessory stem cell subset and erythroid cells Molecule 1 (DNAM-1), also known as CD239 a protein, Basal Cell Adhesion PTA1, expressed on T cells, NK cells, Molecule (B-CAM), expressed on ker- monocytes and platelets atinocyes and erythroid cells; carries the CD227 MUC.1, a transmembrane glyco- Lutheran (Lu) blood group antigens protein, also known as epithelial mem- CD240CE a red cell antigen of the Rh brane antigen, binds to CD169, expressed system, Rh30CE on a stem cell subset, immature erythroid CD240D a red cell antigen of the Rh cells, activated T cells, plasma cells, system, Rh30D epithelial cells and glandular epithelium CD240DCE Rh30D/CE, cross-reactive CD227 is expressed on adenocarci- monoclonal antibodies detecting Rh noma cells, in most plasma cell neo- antigens on erythroid cells HAE-C 01/13/2005 05:10PM Page 69

CDK9 69

CD241 RhAg, expressed on erythroid CDK3 a gene, Cyclin-Dependent Kinase cells 3, gene map locus 17q22-qter, encodes a CD242 Intercellular Adhesion Molecule- kinase activated by cyclin E which regu- 4 (ICAM-4), expressed on erythroid cells; lates G1-S transition during the cell cycle the LW blood group glycoprotein CDK4 a gene, Cyclin-Dependent Kinase CD243 a protein, Multidrug Resistance 1 4, gene map locus 12q14, encodes a protein (MDR-1), expressed on stem cells and kinase activated by the D-type cyclins progenitor cells; its gene is ampliﬁed and is involved in the control of cell leading to overexpression in several drug proliferation during the G1 phase of resistant leukaemia cell lines the cell cycle; inhibited by p16(INK4A) CD244 a protein, 2B4, expressed on NK (see CDKN2A); polymorphisms in the cells and a T-cell subset, a receptor for the p16(INK4A) binding domain of CDK4 product of the SAP gene are associated with a predisposition to CD245 a protein, p220/240, expressed on melanoma a T-cell subset CDK4B inhibitor Cyclin-Dependent Kin- CD246 anaplastic lymphoma kinase, ase 4 inhibitor B, see CDKN2B expressed by T cells CDK6 a gene, Cyclin-Dependent Kinase CD247 T-cell receptor zeta chain, 6, also known as ‘PLSTIRE’ (after the expressed on T cells and NK cells practice of naming CDC2-related kinases CDC2 see CDK1 on the basis of the amino acid sequence CDCREL a gene, Cell Division Cycle of the region corresponding to the con- Related; also known as hCDCre and served PSTAIRE motif of cdc2); gene peanut-like 1; gene map locus 22q11.2, map locus 7q21; encodes a protein act- encodes a member of the septin family of ivated by D-type cyclins, promoting GTPase proteins which are thought to transition from G1 to S phase of the cell play a role in cytokinesis; the gene over- cycle; dysregulated: laps with that encoding platelet glycopro- • by proximity to IGH in t(7;14)(q21;q32) tein Ib, which is encoded on the same DNA associated with less than 5% of cases of strand in the same orientation; CDCREL splenic lymphoma with villous lympho- contributes to the MLL-hCDCre fusion cytes/splenic marginal zone lymphoma gene in acute myeloid leukaemia associ- • by proximity to κ in t(2;7)(p12;q21) ated with t(11;22)(q23;q11.2) associated with a lower percentage of CDK cyclin-dependent kinase cases CDK1 a gene, Cyclin-Dependent Kinase CDK7 a gene, Cyclin-Dependent Kinase 1, also known as Cell Cycle Controller 7, also known as kinase subunit of CAK, CDC2 (from the yeast homologue, cdc2— CAK1, gene map locus 2p15-cen, encodes cell division cycle); gene map locus 10q21.1; a serine/threonine kinase; together with universally expressed, encodes a catalytic cyclin H, forms CDK-activating kinase subunit of a protein kinase complex, the (CAK), which phosphorylates several M-phase promoting factor, that controls other CDKs and associates with the the transition from G1 to S phase and general transcription factor TFIIH from G2 to the M phase of the cell cycle; CDK8 a gene, Cyclin-Dependent Kinase activated by taxol which leads to G2/M 8, also known as K35, gene map locus phase arrest and apoptosis in vitro 13q12; encodes a serine-threonine kinase CDK2 a gene, Cyclin-Dependent Kinase which, along with cyclin C, forms part of 2, also known as p33(CDK2); gene map the RNA polymerase II holoenzyme locus 12q13; expressed late in G1 or in complex; associates with the TAX protein early S phase of the cell cycle, slightly of human T-cell lymphotropic virus type before CDC2; small-molecule inhibi- I (HTLV-I) tors of CDK2 have been investigated for CDK9 a gene, Cyclin-Dependent Kinase prevention of chemotherapy-induced 9, also known as PITALRE (after the alopecia practice of naming cdc2-related kinases HAE-C 01/13/2005 05:10PM Page 70

70 CDKI

Table 5 Cyclin-dependent kinase inhibitors – proteins and genes.

CDKI Gene

Preferred designation Alternative designations Family Protein and location

Cip/Kip family p21Cip1/Waf1 CDKN1A at 6p21.2 WAF1, CIP, CDKN1 p27Kip1 CDKN1B at 12p13 KIP1 p57Kip2 CDKN1C at 11p15.5 KIP2 INK4 family p16INK4A CDKN2A at 9p21 p16(INK4A), CDK4 inhibitor, CDKN2 p15INK4B CDKN2B at 9p21 p15(INK4B), CDK4B inhibitor p18INK4C CDKN2C at 1p32 p18(INK4C) p19INK4D CDKN2D at 19p13 P19(INK4D)

on the basis of the amino acid sequence and p57 (see Table 5); gene map locus of the region corresponding to the con- 11p15.5, encodes p57Kip2, an inhibitor served PSTAIRE motif of cdc2), gene of several cyclin G/CDK complexes; map locus 9q34.1; encodes a serine- down-regulation of the gene is necessary threonine kinase which associates with for cells to enter cell cycle; the locus is cyclin T1 to form transcription elonga- genomically imprinted—the patern- tion factor, P-TEFb, an essential cofactor ally inherited allele is transcriptionally for the human immunodeﬁciency virus repressed and methylated; mutations in (HIV-1) transactivator, Tat; a target for this gene lead to Beckwith–Wiedemann ﬂavopiridol and related anticancer drugs syndrome, a familial disorder character- CDKI cyclin-dependent kinase inhibitor ized by neonatal hypoglycaemia and CDKN1 see CDKN1A subsequent mental retardation, macro- CDKN1A a gene, Cyclin-Dependent glossia and other organomegaly, endo- Kinase Inhibitor 1A, also known as crine disorders and a propensity to Wildtype p53-Activated Fragment 1— rhabdomyosarcoma and hepatoblastoma WAF1, Cdk-Interacting Protein 1—CIP, CDKN2 see CDKN2A CDKN1 and p21 (see Table 5); gene map CDKN2A a gene, Cyclin-Dependent locus 6p21.2; encodes a potent, tight- Kinase Inhibitor 2A, also known as binding inhibitor of CDKs, p21Cip1/Waf1; p14(ARF), p16(INK4A), CDK4 inhi- mediates a p53-induced G2 arrest in the bitor, CDKN2 and Multiple Tumour cell cycle in response to DNA damage; Suppressor 1—MTS1 (see Table 5); gene expression in small cell lung cancer pre- map locus 9p21, a candidate tumour dicts a favourable outcome suppressor gene; this locus gives rise to 2 CDKN1B a gene, Cyclin-Dependent Kinase transcripts from different promoters Inhibitor 1B, also known as KIP1 and encoding p16INK4a and p14ARF (see ARF), p27; gene map locus 12p13; encodes a each with a unique 5′ exon; the p16 pro- CDK inhibitor, p27Kip1, which regulates tein binds to CDK4, inhibits its interac- the G1/S transition of the cell cycle tion with cyclin D and promotes passage (see Table 5); expressed at high levels in through the G1 phase of the cell cycle; quiescent cells, levels decline on mitogen CDKN2A often undergoes homozyg- induction; a major transcriptional target ous deletion, together with deletion of of AFX and other forkhead proteins; low CDKN2B, in B-lineage (15%) and, even levels of p27 protein have been linked more frequently, T-lineage (80%) acute with poor prognosis in gastric lymphoma lymphoblastic leukaemia; homozygous CDKN1C a gene, Cyclin-Dependent deletion is also common in lymphoid blast Kinase Inhibitor 1C, also known as KIP2 crisis of chronic granulocytic leukaemia HAE-C 01/13/2005 05:10PM Page 71

central retinal vein occlusion 71

and is associated with transformation of cDNA complementary DNA a low grade to a high grade lymphoma; CDX2 a gene, Caudal-type homeobox hemizygous and homozygous deletions transcription factor 2, also known as CDX3 are common in mantle cell lymphoma; and insulin-regulating transcription factor; germline mutations at this locus (e.g. gene map locus 13q12.3, encodes a home- p16Leiden) are seen in familial atypical obox transcription factor similar to the multiple mole–melanoma syndrome, and Drosophila gene, caudal; normally ex- in kindreds with familial melanoma and pressed in human jejunal, ileal and colonic pancreatic cancer or neural tumours; mucosa, but not in gastric mucosa; expres- together with CDKN2B. This gene is sion in the stomach has been linked to repressed by hypermethylation in a var- intestinal metaplasia in atrophic gastritis; iety of haematological and solid tumours, contributed to an ETV6-CDX2 fusion the biological significance of this being gene in acute myeloid leukaemia associ- unclear as hypermethylation is seen in ated with t(12;13)(p13;q12); also mutated some normal somatic tissues in some cases of colorectal cancer CDKN2B a gene, Cyclin-Dependent C/EBPε a gene at 14q11.2, CCAAT/ Kinase inhibitor 2B, also known as Enhancer-Binding Protein gene ε, encod- p15(INK4B) and Multiple Tumour ing CCAAT/enhancer-binding protein; Suppressor 2—MTS2 (see Table 5); gene homozygosity for mutations of the gene map locus 9p21, a candidate tumour sup- lead to neutrophil specific granule protein pressor gene; encodes p15INK4B, a protein deficiency; up-regulated by the CBFα2− that inhibits cyclin-CDK4 and cyclin ETO fusion protein in AML with CDK6 complexes and thus negatively t(8;21)(q22;q22) regulates cell proliferation; often under- cell the basic unit of every living organism, goes homozygous deletion, together with whether a unicellular micro-organism or deletion of CDKN2A, in B-lineage and, a complex multicellular organism such as even more frequently, T-lineage acute man lymphoblastic leukaemia; homozygous cell cycle the progress of the cell though deletion of both genes is also common in four phases of growth (G1), synthesis of lymphoid blast crisis of chronic granulo- DNA (S), further growth (G2) and mito- cytic leukaemia; occasionally deleted in sis (M); cells that are not in cycle are multiple myeloma; together with CDKN2A described as being in G0 (Fig. 15) this gene is repressed by hypermethyla- cell-mediated immunity immunity tion in a variety of haematological and mediated by T lymphocytes and natural solid tumours, the biological significance killer cells of this being unclear as hypermethylation cellular haemoglobin concentration is seen in some normal somatic tissues mean (CHCM) an estimation of the CDKN2C a gene, Cyclin-Dependent Kinase concentration of haemoglobin in indi- inhibitor 2C, also known p18(INK4C) vidual erythrocytes derived from deter- (see Table 5); gene map locus 1p32; encodes mination of the optical characteristics of p18INK4C, a cyclin-dependent kinase inhi- individual cells in an automated blood bitor most abundant in skeletal muscle cell counter but present in other tissues; inhibits centiMorgan (cM) the unit of genetic CDK6; homozygous deletion of this gene distance, the distance separating two loci occurs in multiple myeloma but generally that have 1% chance of recombination alterations of this gene in cancer are rare central nervous system (CNS) the CDKN2D a gene, Cyclin-Dependent Kinase brain and the spinal cord inhibitor 2D, also known p19(INK4D) central retinal vein occlusion occlu- (see Table 5); gene map locus 19p13; sion of the central vein of the retina, may encodes p19INK4D, an inhibitor of CDK4 result from hyperviscosity in multiple and CDK6; alterations of this gene in myeloma or other plasma cell dyscrasia, cancer are rare or from hyperhomocysteinuria, factor V HAE-C 01/13/2005 05:10PM Page 72

72 centroblast

Figure 15 The cell cycle. of the long and short arms of a chromo- The phases of the cell cycle: G1 and G2 are phases some (see Fig. 9, p. 22) of cell growth, G1 being to the ‘Gap’ before DNA centromeric pertaining to the centromere synthesis and G2 being the ‘Gap’ before mitosis, centromeric probe a complementary S represents synthesis of DNA and M represents mitosis; cells in G0 are non-cycling. oligonucleotide sequence capable of binding to the centromere of a specific chromosome G0 M CEP1 a gene, Centrosomal Protein 1, also designated FAN and Centrosome- associated Protein 110—CEP110; gene map locus 9q33; encodes centrosome- associated protein 110; contributes to the CEP100-FDGFR1 gene in the myelo- G2 G1 proliferative disorder associated with t(8;9)(p12;q33) (see 8p11 syndrome) CEP110 see CEP1 cerebrospinal fluid (CSF) the clear fluid surrounding the brain and spinal cord S CGD chronic granulomatous disease CGH comparative genomic hybridization CHAD chronic cold haemagglutinin disease Leiden, the G20210A mutation in the Chagas’ disease a parasitic disease F2 (prothrombin) gene, protein C defi- prevalent in South America, consequent ciency, protein S deficiency or antithrom- on infection by Trypanosoma cruzi bin deficiency or the presence of a lupus Charcot–Leyden crystals crystals in anticoagulant the shape of two elongated pyramids, in centroblast a large, nucleolated follicle tissue section and bone marrow smears centre B lymphocyte (see Fig. 13, p. 30) appearing like elongated diamonds, formed centroblastic/centrocytic lymphoma by crystallization of the granule contents an alternative designation (in the Kiel of eosinophils, seen in tissues in reactive classification and the REAL classification) eosinophilia and eosinophilic leukaemia of follicular lymphoma of the WHO CHCM cellular haemoglobin concentra- classification; lymphoma cells resemble tion mean normal centrocytes and centroblasts Chédiak–Higashi syndrome a serious, centroblastic lymphoma a large cell autosomal recessive condition character- lymphoma of B lineage with cells resem- ized by giant lysosomes in various cells bling normal centroblasts; a subtype of leading to large abnormally staining diffuse large B-cell lymphoma in the granules in granulocytes, monocytes and WHO classification lymphocytes; other features include par- centrocyte a small follicle centre B lym- tial albinism, platelet dysfunction, recur- phocyte (see Fig. 13, p. 30) rent infections and infection-triggered centrocytic lymphoma a somewhat haemophagocytosis; it results from muta- ambiguous term including lymphomas tion in the CHS1 gene (also known as with cells analogous to normal follicle LYST—Lysosomal Trafficking regulator centre cells but also sometimes used to gene) refer to mantle cell lymphoma (designated cheilosis scaling and fissuring of the lips ‘diffuse centrocytic lymphoma’ in the (see angular cheilosis) Kiel classification) chemokine a group of at least 46 small centromere the constricted region of a secreted polypeptides (8-14 kD) assigned nuclear chromosome, to which the spindle to one of four chemokine families on the fibres attach during division; the junction basis of the arrangement of the first two HAE-C 01/13/2005 05:10PM Page 73

chemokine 73

Figure 16 Chromatin structure and physiology. The DNA in the nucleus is packaged into a nucleoprotein structure called chromatin. The basic unit of chromatin is the nucleosome, which consists of 146bp of DNA wrapped around a core made of two copies of each of four histone proteins H2A, H2B, H3 and H4. The chromatin in untranscribed regions of the genome is densely packed (heterochromatin); that in transcriptionally active regions is more accessible (euchromatin). Every cell type has a pattern of chromatin packing that is unique to its spectrum of gene expression, and which is maintained after cell division. Chromatin must be decompacted in order for the transcriptional machinery to access genes and for transcription to occur. This reversible process is achieved by coregulator proteins, which either reposition nucleosomes to allow transcription factors access to promoter regions (nucleosome remodelling complexes, NRCs), or covalently modify histone proteins. Covalent modiﬁcation includes acetylation and deacetylation, catalysed by histone acetylases (HATs) and histone deacetylases (HDACs) respectively; and arginine and lysine methylation, catalysed by histone arginine methytransferases (H-AMTs) and histone lysine methytransferases (H-LMTs). Histone acetylation and arginine methylation are associated with activation of transcription; deacetylation is associated with repression of transcription; lysine methylation can be associated with either activation or repression. It is not known whether methylation is reversible. The MOZ protein is an example of a histone acetylase; TEL and the TEL-AML1 fusion proteins can recruit histone deacetylases.

Heterochromatin

Euchromatin

HDACs HATs

CompactionH-AMTs Decompaction H-LMTs H-LMTs NRCs NRCs

Nucleosome

Transcription HAE-C 01/13/2005 05:10PM Page 74

74 chemokine receptor

aminoterminal cysteine residues: CXC or lymphoma comprising Cyclophosphamide, α chemokines (CXCL1–CXCL16) which Hydroxydaunorubicin (doxorubicin), vin- have two cysteines separated by another cristine (‘Oncovin’) and Prednisolone amino acid; CC or β chemokines (CCL1– Christmas disease a haemorrhagic dis- CCL28) which have two adjoining cys- order resulting from factor IX deficiency, teines; C (XCL1) and CX3C, which has named after the first diagnosed patient cysteines separated by three amino acids (see haemophilia B) (CX3CL1); the various chemokines bind chromatid one of the two side by side chemokine receptors, thus mediating replicas produced by chromosome replic- intravascular adhesion of leukocytes ation in either mitosis or meiosis (see and migration of leucocytes into and Fig. 9, p. 22); during the processes of within the intravascular space; they also mitosis and meiosis the two chromatids influence angiogenesis separate from each other and move to chemokine receptor a group of seven daughter cells transmembrane chemokine receptors chromatin nuclear DNA complexed grouped into four families: CX chemo- with histones and other nuclear proteins kine receptors (CXCR1–CXCR6); CC (Fig. 16, p. 73) chemokine receptors (CCR1–CCR11), C chromatogram visual representation of chemokine receptor (XCR1) and CX3C the results of chromatography chemokine receptor (CX3CR1) chromatography a method of separat- chemotaxin a molecule which attracts ing proteins from each other by means of leucocytes to the site of inflammation physical characteristics, such as molecu- chemotaxis the process by which leuco- lar weight, charge or hydrophobicity, or cytes are attracted to sites of inflammation by means of differing affinity for lectins, chemotherapy the drug treatment of antibodies or other proteins; the proteins infection or cancer move through an absorbent column and CHI Commission for Health Improvement emerge after different periods of time CHIC2 a gene, Cysteine-rich Hydro- chromodomain a protein motif found phobic domain 2, also known as BTL— in structural components of large macro- Brx-like gene Translocated in Leuk- molecular chromatin complexes and pro- aemia, gene map locus 4q11-12; encodes teins involved in remodelling chromatin a member of a recently described fam- structure (see also bromodomain) ily of small, palmitoylated, membrane- chromogranin an antigen expressed by associated proteins, characterized by the tumours showing neuroendocrine differ- presence of a cysteine-rich hydrophobic entiation, e.g. carcinoid tumour, small (CHIC) motif; contributes to a BTL/ cell carcinoma of the lung, neuroblastoma CHIC2-ETV6 fusion gene in acute myeloid chromosome a linear structure in the leukaemia associated with t(4;12)(q11- nucleus of a cell, composed of a long paired 12;p13) strands of DNA that carries genetic chimaerism the presence of two gen- information; human beings have 23 pairs etically distinct populations of cells; may of chromosomes, 22 pairs of autosomes result from constitutional mosaicism or and two sex chromosomes (see Fig. 31, follow stem cell transplantation p. 110) CHIMP see CHI chromosome banding a process of chlorambucil an alkylating agent used staining chromosomes, producing light in the treatment of chronic lymphoid and dark bands, so that individual chro- leukaemias and low grade lymphomas mosomes can be recognized (see Q band- chloroacetate esterase see naphthol ing, G-banding and Fig. 31, p. 110) AS-D chloroacetate esterase chromosome painting a technique chloroma see granulocytic sarcoma for identifying part or all of individual CHOP a chemotherapeutic regimen com- chromosomes by the use of a combina- monly used in the treatment of high grade tion of probes that bind with a high level HAE-C 01/13/2005 05:10PM Page 75

clinical governance 75

of specificity to all or part of a single pair for all chronic leukaemias of myeloid of chromosomes lineage chronic developing over a period of time chronic myelomonocytic leukaemia and progressing slowly (CMML) a chronic leukaemia with chronic cold haemagglutinin disease monocytic and usually also granulocytic (CHAD) a chronic disease character- differentiation, in the FAB classification ized by cold-induced peripheral vascular one of the myelodysplastic syndromes and obstruction and haemolytic anaemia, con- in the WHO classification one of the my- sequent on production of a cold agglutinin eloproliferative–myelodysplastic disorders by a clone of neoplastic B lymphocytes chronic neutrophilic leukaemia a chronic eosinophilic leukaemia a chronic leukaemia with predominantly chronic leukaemia with predominantly neutrophilic differentiation eosinophilic differentiation chronic obstructive airways dis- chronic granulocytic leukaemia a ease (COAD) chronic bronchitis and specific type of chronic myeloid leukaemia emphysema, may lead to chronic hypoxia characterized by the presence of t(9;22) and secondary polycythaemia which leads to formation of the Philadel- chronic obstructive pulmonary dis- phia chromosome (22q–) (see Fig. 31, ease (COPD) a synonym for chronic p. 110); often known as ‘chronic myeloid obstructive airways disease leukaemia’ CHS1 the gene, gene map locus 1q42.1- chronic granulomatous disease an q42.2, also known as LYST, encoding a inherited defect in neutrophil function lysosomal trafficking regulator, muta- resulting from mutation in one of the four tions of which can lead to Chédiak– genes encoding phagocyte adenine dinu- Higashi syndrome cleotide phosphate (NADPH) oxidase Churg–Strauss syndrome a variant subunits; complete absence or malfunc- of polyarteritis nodosa characterized by tion of NADPH oxidase leads to the lack eosinophilia and pulmonary infiltration of a respiratory burst and consequent CIP1 see CDKN1A defective killing of bacteria by neutro- cirrhosis chronic liver disease character- phils; genes implicated are CYBB (sex- ized by nodularity and scarring linked recessive inheritance) and CYBA, cis on the same chromosome NCF1 and NCF2 (autosomal recessive cis-acting a DNA sequence that affects inheritance) the expression of a gene on the same chronic leukaemia a type of leukaemia chromosome but not on the homologous in which there is differentiation of leuk- chromosome aemic cells to mature cells and which cisplatin an anti-cancer drug, used par- causes death in months or years rather ticularly in treating germ cell tumours than in weeks citrate a salt of citric acid, used as a chronic lymphocytic leukaemia (CLL) calcium-binding anticoagulant for blood a chronic lymphoid leukaemia of B lineage specimens for coagulation tests with characteristic cytological, histolog- cladribine a nucleoside analogue used ical, immunophenotypic and cytogenetic in treating hairy cell leukaemia features class switching a process occurring chronic lymphoid leukaemias a in germinal centres in which B lympho- generic term for chronic leukaemias of cytes switch from expressing IgM/IgD to B, T or NK lineage expressing IgG, IgA or IgE chronic myelogenous leukaemia a clear cell carcinoma a carcinoma in which synonym for chronic granulocytic leuk- stained cells appear to have empty cyto- aemia or chronic myeloid leukaemia plasm, often originating in the kidney chronic myeloid leukaemia (CML) (i) clinical governance a process through an alternative designation of chronic which NHS organizations are account- granulocytic leukaemia (ii) a generic term able for improving the quality of service, HAE-C 01/13/2005 05:10PM Page 76

76 clonal

safeguarding high standards and creating the coagulation factors appear to interact an environment in which excellence in in vitro (Fig. 17) clinical care will ﬂourish (UK) coagulation factor one of the plasma clonal pertaining to a clone proteins required for clotting of blood, clonal selection the process by which either in vitro or in vivo germinal centre B cells that have been coagulation network a concept of exposed to antigen are rescued from how coagulation factors interact to cause apoptosis and thus selected for survival blood clotting in vivo (Fig. 18, p. 78) and proliferation if they produce anti- cobalamin the common chemical struc-

body with a high affinity for the relevant ture of different forms of vitamin B12, e.g. antigen hydroxocobalamin, cyanocobalamin clone a population of cells derived from coccidioidomycosis a disease resulting a single cell from infection by the fungus Coccidioides cloning production of a clone from a immitis single cell; popularly indicates produc- codon a triplet of nucleotides, in DNA tion of a new individual from a single cell or RNA, which codes for a specific amino CLTC a gene, Clathrin, heavy polypep- acid or serves as a termination signal; tide, gene map locus 17q23; one of two there are 61 codons encoding 20 amino closely related genes encoding clathrin acids and 3 codons which act as termina- heavy chain, which is thought to contrib- tion or stop codons ute to a CLTC-ALK fusion gene, pro- coeliac disease a disease resulting from bably associated with t(2;17)(p23;q23), in hypersensitivity to the wheat protein, a minority of patients with anaplastic gluten, leading to chronic malabsorption large cell lymphoma and splenic atropy; may cause deficiency

CLTCL a gene, Clathrin, heavy polypeptide- of vitamin B12, folic acid or iron or haem- like 1 also known as clathrin, heavy poly- orrhage as a result of vitamin K deficiency peptide D, CLTD and CLH22; gene map cohesive a growth pattern in which cells locus 22q11.2; encodes a ubiquitously form a compact masses expressed protein very similar to CLTC, cohort a subgroup of individuals selected alternative transcripts have been ident- for study, born or recruited at the same ified in several tissues, but the significance time and followed up longitudinally of this is unclear; was thought to have coiled coil a protein motif characterized contributed to a CLTCL-ALK fusion by an apolar residue occurring every sev- gene in anaplastic large cell lymphoma enth base; functions as a protein subunit with a presumptive t(2;22)(p23;q11); in oligomerization site fact, this is now thought to have been a coincidence occurring at the same CLTC-ALK fusion gene, probably asso- time, e.g. when two cells pass through a ciated with t(2;17)(p23;q23); this usually counting chamber of a flow cytometer ubiquitously expressed gene is not expres- simultaneously sed in the majority of meningiomas coincidence correction correction of a cM a centiMorgan cell count for coincidence CMV cytomegalovirus cold agglutinin an agglutinating anti- COAD chronic obstructive airways disease body with maximum activity at low coagulation blood clotting temperatures coagulation cascade a concept of how cold agglutinin disease (CHAD) cold- coagulation factors interact to cause blood induced haemolytic anaemia and vascu- clotting; each coagulation factor is con- lar obstruction caused by the presence of ceived as initiating activation of another a cold agglutinin coagulation factor lower down the ‘coag- collagen a fibrillar protein, synthesized ulation cascade’ with amplification of the by fibroblasts, which is apparent as process at each step; the concept of the eosinophilic fibres on a haematoxylin coagulation cascade is based on how and eosin-stained tissue section HAE-C 01/13/2005 05:10PM Page 77

colony-forming unit-Mega (CFU-Mega) 77

Figure 17 The coagulation cascade. The coagulation cascade is the sequential in vitro activation of coagulation factors following interaction with a foreign surface. Factors XII, XI, IX, X and II are intrinsic pathways factors which are converted to serine proteases and act on subsequent factors in the cascade; factors VIII and V are cofactors; the extrinsic pathway is activated by the interaction of factor VII and tissue factor. The activated partial thromboplastin time tests the intrinsic pathway; coagulation is initiated by contact with particulate matter such as kaolin and a ‘partial thromboplastin’ (such as cephalin) acts as a substitute for platelet phospholipid (Phl). The prothrombin time tests the extrinsic pathway, coagulation being initiated by addition of a ‘complete thromboplastin’, which acts as a substitute for tissue factor. The thrombin time, in which thrombin is added to plasma, tests the final step of the common pathway, the conversion of fibrinogen to fibrin.

Contact with foreign surface or particle, e.g. kaolin

XII XIIa

XI XIa

VII + 'Complete IX IXa thromboplastin'

VIII VIIIa VIIa Phl Intrinsic 2+ pathway Ca X Xa Extrinsic V Va pathway Phl Ca2+ Common pathway II IIa (thrombin)

Fibrinogen Fibrin

colloid a suspension of ﬁne insoluble give rise to a colony of erythroid cells when particles; colloids for transfusion in- cultured in vitro (see Fig. 41, p. 122) clude human albumin or plasma protein colony-forming unit-granulocyte fraction and various synthetic plasma (CFU-G) a progenitor cell that can substitutes give rise to a colony of cells of granulo- colony a group of cells derived from a cyte lineage when cultured in vitro (see single cell when progenitor cells are Fig. 41, p. 122) cultured in vitro colony-forming unit-granulocyte/ colony-forming unit (CFU) a progen- macrophage (CFU-GM) a progenitor itor cell which can give rise to a colony cell that can give rise to a mixed colony of cells on in vitro culture, e.g. CFU-E, of cells of both granulocyte and mono- CFU-G (see Fig. 41, p. 122), or when cyte lineages when cultured in vitro (see injected into an experimental animal Fig. 41, p. 122) colony-forming unit-erythroid (CFU- colony-forming unit-Mega (CFU-Mega) E) an erythroid progenitor cell that can a megakaryocyte progenitor that can give HAE-C 01/13/2005 05:10PM Page 78

78 colony-stimulating factor 1 (CSF1)

Figure 18 The coagulation network. A concept of how coagulation factors interact in vivo. The interaction of factor VII and tissue factor leads to activation of both the extrinsic and intrinsic pathways, which are more closely related than appears from in vitro tests of coagulation; thrombin (factor IIa) is involved in three positive feedback loops that act on factors of the intrinsic pathway; the net result is activation of factor XIII and conversion of fibrinogen to fibrin monomer plus fibrinopeptides A and B; fibrin monomers spontaneously associate to form fibrin polymer which is then stabilized by factor XIIIa-mediated cross-linking between monomers.

XI XIa

TF + VII IX IXa

VIII VIIIa VIIa Phl Ca2+

XXa

V Va Phl Ca2+ XIII

II IIa (prothrombin) (thrombin) XIIIa

Spontaneous association

Fibrinogen Fibrin Fibrin Stable monomer polymer cross-linked + fibrin fibrinopeptides A and B

rise to a colony of cells of megakaryocyte and improving the quality of patient care lineage when cultured in vitro (see Fig. 41, in England and Wales p. 122) common acute lymphoblastic leuk- colony-stimulating factor 1 (CSF1) aemia acute lymphoblastic lenkaemia see macrophage colony stimulating with expression of the common ALL factor antigen, CD10 (and, according to the combined esterase a combined stain EGIL classiﬁcation, without expression for chloroacetate esterase and non-speciﬁc of cytoplasmic µ chain) esterase common lymphoid–myeloid progeni- Commission for Health Improvement tor a stem cell capable of giving rise to (CHI or CHIMP) a public body (UK), all lymphoid and myeloid cells, see also established with the aim of monitoring pluripotent stem cell HAE-C 01/13/2005 05:10PM Page 79

compound heterozygote 79

common lymphoid progenitor a complementarity-determining region stem cell capable of giving rise to all that part of an IGH, IGK, IGL or TCR lymphoid cells locus that encodes the antigen-binding common myeloid progenitor a stem area of the immunoglobulin molecule or cell capable of giving rise to all myeloid T-cell receptor cells, see also multipotent myeloid stem complementary DNA (cDNA) single- cell stranded DNA synthesized from a mRNA common pathway that part of the template by means of reverse transcriptase coagulation cascade that is common to complement fixation the process by the intrinsic pathway and the extrinsic which complement components are pathway bound to the Fc part of antibody common variable immunodeficiency molecules, the antibody molecules being genetically heterogeneous, late onset already either complexed to antigen or immunoglobulin deficiency; some patients aggregated; complement can be fixed by have mutations in the X-linked agamma- IgM, IgG1, IgG3 and, to a lesser extent, globulinaemia gene (XLA), the X-linked IgG2 antibodies (X-HIM) or autosomal hyperimmuno- complement system a group of globulin M (HIM) syndrome genes or the plasma and cell surface proteins that SH2DIA gene participate in both innate and adaptive compact bone solid bone with only immune responses and act as a bridge small interstices, as in the cortex of a between the two; the complement system bone also amplifies the B-cell response to comparative genomic hybridization antigens and helps remove immune com- (CGH) an in situ hybridization tech- plexes from plasma and both immune nique used in the characterization of complexes and apoptotic cells from tis- unbalanced chromosomal abnormalities sues; when antibodies aggregate or form in tumour cells; a mixture of normal and an immune complex with antigens, there test DNA, labelled with two different is sequential binding and activation fluorochromes, is hybridized to normal of complement components, leading human metaphase chromosomes, so that ultimately to damage or destruction of under- or over-representation of sequences cells—the classical pathway of comple- of DNA can be detected as areas where ment activation; the alternative and lectin one or other colour dominates; particul- pathways of complement activation are arly useful for the analysis of archival and part of the body’s innate immune poor quality samples, and in tumours responses, being activated by microbial with complex karyotypes cells walls and microbial carbohydrates compatible able to exist together, e.g. respectively (Figs 19 and 20, pp. 80 and 81) blood that an be transfused without complete blood count (CBC) of a giving rise to a transfusion reaction synonym for full blood count (FBC), the competitive PCR a semi-quantitative latter being the internationally agreed PCR technique in which there is co- terminology amplification of an internal control, the complete remission (CR) the disap- competitor, present in graded concentra- pearance of all clinical and pathological tions together with target gene signs of a disease, although minimal complement one or more components residual disease may still be detectable by of the complement pathway (see comple- immunophenotypic or molecular genetic ment system) techniques complement activation the sequential compound heterozygote a person activation of complement components with two abnormal but different alleles of through the classical, alternate or mannose- a given gene, e.g. compound heterozygos- binding lectin complement pathways (see ity for βS and βC, sickle cell/haemoglobin Figs 19 and 20, pp. 80 and 81) C disease HAE-C 01/13/2005 05:10PM Page 80

80 compound heterozygote

Figure 19 The classical complement pathway.

In the classical complement pathway the binding of immunoglobulin (IgG1, IgG2, IgG3 or IgM) to antigen leads to binding of the Fc end of immunoglobulin molecules, if in close proximity, to the C1q,C1r,C1s complex with resultant activation of C1s. C1s, in turn, cleaves C4 and C2 with one product of each reaction combining to produce a C4b2a, a C3 convertase. C3 convertase cleaves C3 to C3a and C3b and then combines with C3b to form C4b2a3b, a C5 convertase. C5 convertase cleaves C5 to C5a and C5b. The latter initiates formation of the membrane attack complex by binding to C6, C7 and C8 with the complex then binding C9 and inserting it into the membrane of the cell bearing the antigen with resultant cell lysis. Cleavage products of various complement components have effects on neutrophils, macrophages, mast cells and smooth muscle cells. C3a and C5a are anaphylatoxins, which cause contraction of smooth muscle cells, degranulation of mast cells and increased vascular permeability. C5a is also chemotactic for neutrophils and macrophages. C3b not only contributes to the formation of C5 convertase but also binds to C3b receptor on neutrophils and macrophages, activating these cells.

Antigen

I8 Cls Cls Clr Clq

C4 C4a + C4b

C2 C2a + C2b

Stabilized by C4b2a properdin (C3 convertase) Neutrophil

C3 C3a + C3b

Macrophage C4b2a3b (C5 convertase)

C5 C5a + C5b

C5b678

C5b6789 (membrane attack complex) HAE-C 01/13/2005 05:10PM Page 81

compound heterozygote 81

Figure 20 The alternative and mannose-binding lectin complement pathways. The alternative complement pathway is initiated by the binding of trace amounts of C3b to the cell walls of Gram-negative bacteria or fungi. C3b binds to factor B and factor D then cleaves bound factor B so that C3bBb is formed. It is stabilized by properdin and acts as a C3 convertase. From this stage the pathway is the same as the classical pathway (see Figure 19). The C3b which is generated can bind to bacterial cell walls thus creating a positive feedback loop. The mannose-binding lectin pathway can be activated by some parasites, fungi, viruses and bacteria with cell walls containing mannose, which bind to mannose-binding lectin (MBL), in the presence of mannose- binding lectin associated proteases 1 and 2 (MASP1 and MASP2). MASP2 is activated and it cleaves C4 and C2 to produce a C3 convertase. It is possible that MASP 1 in the complex also has C3 convertase activity. Once C3 convertase is formed, the pathway is the same as the classical pathway.

Alternative Mannose-binding lectin pathway pathway Some parasites, viruses, fungi, Gram-negative bacterial cell walls containing bacterium mannose or fungus

MASP1 C3b MASP2 Factor B MBL

C3bB C4 C4a + C4b

C2 C2a + C2b D ?

Properdin C3bBb + Ba C4b2a stabilizes (C3 convertase) (C3 convertase)

C3 C3a + C3b C3 C3a + C3b

C3b3bBb C4b2a3b (C5 convertase) (C5 convertase)

C5 C5a + C5b C5 C5a + C5b

C5b678 C5b678

C5b6789 C5b6789 HAE-C 01/13/2005 05:10PM Page 82

82 computerized axial tomography, computed tomography (CAT scan, CT scan)

Figure 21 A CT scan of the abdomen. designate a group of hereditary haemo- A computerized axial tomogram (CT scan) of the lytic anaemias with no distinguishing abdomen showing massive enlargement of the morphological features, mainly caused kidneys, resulting from infiltration, in a child with by defects in the glycolytic pathway acute lymphoblastic leukaemia. congenital X-linked agammaglobulinaemia an inherited immune deficiency syndrome resulting from a mutation in the BTK (Bruton tyrosine kinase) gene at Xq21.3 conjugated bilirubin bilirubin which has been conjugated to glucuronic acid, an increased concentration in the serum being indicative of biliary obstruction or cholestasis rather than haemolysis (see Fig. 11, p. 28) consanguinity having a common an- cestor and thus having some genes in common constitutional being part of the consti- tution of an individual, implies inherited constitutional pure red cell aplasia computerized axial tomography, an alternative designation of Diamond– computed tomography (CAT scan, Blackfan syndrome CT scan) a method of imaging using Consumer Protection Act 1987 a UK computerized X-ray analysis to produce Act of Parliament that means that manu- a cross-sectional image of part of the facturers—including manufacturers, sup- body (Fig. 21) pliers and keepers of blood products— concordance agreement are liable for harm resulting from a defect confidence interval the range within in the product; it governs all aspects of which it is predicted that 95% of measure- blood and blood product provision from ments will fall if repeated measurements blood donation to the hospital blood are made bank congenital present from birth; often, consumption coagulopathy an altern- but not necessarily, inherited ative designation of disseminated intra- congenital autosomal recessive vascular coagulation agammaglobulinaemia severely contact activation activation of the reduced immunoglobulin synthesis and intrinsic pathway of coagulation by con- reduced humoral immunity, a genetically tact with a foreign surface heterogeneous syndrome some cases of contact factor a factor capable of initi- which result from a mutation of the µ chain ating the intrinsic coagulation pathway gene at 14q32, the surrogate light chain contigs groups of clones representing gene (λ5/14) at 22q11.2, the Igα (CD79a) overlapping genomic regions gene at 19q13.2 or the gene encoding the continuous ambulatory peritoneal B-cell linker adaptor protein dialysis (CAPD) a method of treating congenital dyserythropoietic anaemia chronic renal failure by inserting dialysis a heterogeneous group of congenital and fluid into the peritoneal cavity inherited dyserythropoietic anaemias, Cooley’s anaemia see β thalassaemia divided into types I, II (HEMPAS) and major III and various other less well-character- Coombs’ test see antiglobulin test ized subtypes COPD chronic obstructive pulmonary disease congenital non-spherocytic haemo- cord blood transplantation trans- lytic anaemia a generic term used to plantation of stem cells obtained from HAE-C 01/13/2005 05:10PM Page 83

CR1 83

Figure 22 Core binding factor. The core binding factors (CBFs) comprise a group of heterodimeric transcription factors, some of which play a major role in the regulation of haemopoiesis: the genes encoding them are a common target for mutation in leukaemia. Each is composed of a non-DNA-binding CBFβ chain and a DNA-binding CBFα chain that contains a structural motif known as the runt domain. The runt domain permits DNA binding to a consensus YGYGGT (Y = C or T) sequence and is also involved in CBFα binding to CBFβ. The interaction of CBFα and CBFβ is thought to increase the DNA binding capacity of the runt domain. There are three CBFα-encoding genes in man, RUNX1 encoding AML1/CBFα2, RUNX2 encoding AML3/ CBFα1 and RUNX3 encoding AML2/CBFα3. CBFα2 is ubiquitously expressed but is expressed at very high levels in haemopoietic tissues, where it activates several genes and is critical for embryonic haemopoiesis. CBFα1 is expressed only in osteoblasts. The function of CBFα3 is unclear but it is known to activate several haemopoietic genes. Both CBFα2 and CBFα1 are known to interact with TLE family proteins (widely expressed transcriptional repressors) via a conserved motif located outside the runt domain. In addition, CBFα2 is known to activate CBP, a histone acetylase, suggesting inhibitory as well as activating functions for these proteins.

CBFβ β CBF CBFα

CBFα Runt domain YGYGGT

CBFα2 Definitive haemopoiesis CBFβ CBFα1 Osteogenesis CBFα3 ? haemopoieisis

the umbilical cord after the placenta correlation coefficient of 1.0 indicates and cord have been separated from the perfect correlation neonate cortex the outer part of an organ, e.g. the core binding factor (CBF) a transcription cortex of a lymph node, kidney, adrenal factor complex which is a heterodimer, gland, bone; the cortex of bone is com- composed of CBFα (coded for by AML1 posed of compact bone, mainly with a —also known as CBFA and RUNX1) lamellar structure and CBFβ (encoded for by CBFB) corticosteroids steroid hormones syn- (Fig. 22) thesized in the cortex of the adrenal coronary artery disease atheroma gland, capable of causing neutrophilia, affecting coronary arteries lymphopenia and eosinopenia coronary occlusion blockage of a cor- cosmid plasmid DNA containing Cos onary artery sites that enable it to be packaged into coronary thrombosis blockage of a phage particles that can then enter bacte- coronary artery by a blood clot, usually ria; DNA sequences complementary deposited on an atheromatous plaque to human DNA sequences serve as a corpuscle a now little-used term for probe erythrocytes and leucocytes coumarin a class of oral anticoagulants, correlation the relationship between acting as vitamin K antagonists, of which two series of observations warfarin is a commonly used example correlation coefficient a mathemat- CR complete remission ical expression of the closeness of the rela- CR1 a gene at 1q32 encoding CD35, a tionship between two series of figures; a complement regulatory protein, the C3b/ HAE-C 01/13/2005 05:10PM Page 84

84 C-reactive protein (CRP)

C4b receptor. that caries the Knops prepared; in some circumstances it can be blood group antigens used for plasma exchange C-reactive protein (CRP) an acute cryptic hidden, as in ‘cryptic translocation’ phase reactant produced by hepatocytes cryptic translocation a translocation under the inﬂuence of interleukin-6 that is detectable by molecular techniques CRF an abbreviation for either chronic but is not detectable by standard chromo- renal failure or corticotrophin-releasing some banding techniques, e.g. because of factor the similarities of the banding patterns of Crohn’s disease an inﬂammatory disease the two chromosomes implicated of the distal small bowel; very extensive cryptococcosis disease resulting from disease or, much more often, treatment infection by the fungus Cryptococcosis

by bowel resection may cause vitamin B12 neoformans deficiency; Crohn’s disease can also result crystal a solid substance arranged in a in iron deficiency and the anaemia of regular three-dimensional structure that chronic disease determines its shape, e.g. haemoglobin C Cromer a minor blood group system, the crystals and Charcot–Leyden crystals antigens being carried on the GPI-linked crystalloid a solution, e.g. saline solu- decay accelerating factor protein tions used for resuscitation crossing over the exchange of sections CSF cerebrospinal fluid of chromatids between homologous pairs CSF1 colony stimulating factor 1 of chromosomes during meiosis CSF1R a gene, Colony-Stimulating crossmatch see crossmatching Factor 1 Receptor, also known as CD115, crossmatching the process of determin- fms mcdonough feline sarcoma viral ing that blood for transfusion is compat- oncogene homologue, FMS; gene map ible with the recipient by tests employing locus 5q33.3; encodes a membrane tyro- the patient’s serum and the donor cells sine kinase of the PDGF receptor family cross-species fluorescence in situ that is the receptor for macrophage hybridization (RxFISH) fluorescence colony-stimulating factor; normally ex- in situ hybridization analysis using probes pressed by monocytes and macrophages; for DNA of another species over-expressed in some types of acute CRP C-reactive protein myeloid leukaemia; allelic loss of c-FMS cryofibrinogen a precipitate that de- has been detected in both acute myeloid velops when plasma is chilled, composed leukaemia and myelodysplastic syndromes mainly of fibrinogen and fibronectin, but though its prognostic significance is unclear α α also containing 1 antitrypsin and 2 CT scan computerized tomography scan macroglobulin and, in some individuals, CTIP2 a gene, COUP Transcription polyclonal immunoglobulins Factor Interacting Protein 2, see BCL11B cryofibrinogenaemia the presence of Cushing’s syndrome a syndrome cryofibrinogen in the plasma; in some resulting from secretion of excess corti- individuals cryoglobulin is also present costeroids by the adrenal gland cryoglobulin a protein which precipit- cutaneous pertaining to the skin ates in the cold cutaneous mastocytosis a disease cryoglobulinaemia the presence of a resulting from infiltration of the skin by cryoglobulin in the circulating blood mast cells without apparent infiltration of cryoprecipitate a blood product that is other organs; the typical skin lesions are prepared by freezing plasma rapidly to referred to as urticaria pigmentosa below –30°C then thawing it slowly cutaneous T-cell lymphoma a T-cell overnight at 4°C; the resultant precipit- lymphoma of the skin; mainly mycosis ate contains factor VIII, factor XIII and fungoides or Sézary syndrome fibrinogen cyanmethaemoglobin the form of cryosupernatant the depleted plasma haemoglobin produced by the addition that is removed when cryoprecipitate is of cyanide-containing reagents to blood, HAE-C 01/13/2005 05:10PM Page 85

cytospin 85

permitting accurate measurement of family inhibiting many CDKs and the haemoglobin concentration INK4 family inhibiting speciﬁcally cyanocobalamin the form of vitamin CDK4 and CDK6 (see Table 5, p. 70)

B12 used for the Schilling test cyclophosphamide an alkylating agent cyanosis blueness of the skin and used for immunosuppression and for mucous membranes, can result from treatment of lymphoma desaturation of haemoglobin (increased cystinosis a metabolic disorder which deoxyhaemoglobin) or the occurrence of leads to deposition of cystine crystals in methaemoglobinaemia tissues including the bone marrow cyanotic heart disease congenital cytochemistry staining of cells by expo- heart disease with mixing of venous (un- sure to chemicals that react selectively with saturated) and arterial (saturated) blood; certain components of certain cells, thus leads to polycythaemia as a consequence aiding in the determining of cell lineage of tissue hypoxia cytogenetics the science of the study of CYBA a gene, gene map locus 16q24, chromosomes α encoding cytochrome b245 polypeptide cytokine a group of low molecular (p22phox), mutation of which can lead to weight soluble proteins that act as mes- chronic granulomatous disease; the pro- sengers within the immune system and tein encoded is one of two subunits of between the immune system and other

ﬂavocytochrome b558 (the other subunit systems, regulating haemopoiesis and being gp91phox) mediating immune and inﬂammatory res- CYBB a gene, gene map locus Xp21.2, ponses and wound healing; they include β encoding cytochrome b245 polypeptide interleukins, chemokines and interferons (gp91phox), mutation of which can lead cytomegalovirus (CMV) a herpesvirus, to chronic granulomatous disease; the which can cause an infectious mononu- protein encoded is one of two subunits of cleosis-like illness and impaired bone

flavocytochrome b558 (the other subunit marrow function, the latter mainly in being p22phox) immunosuppressed subjects cyclical neutropenia periodically cytopenia reduction in the number of recurring neutropenia, usually with a cells in the peripheral blood, e.g. neu- cycle of 19–21 days tropenia, thrombocytopenia, pancytopenia cyclin one of a class of proteins whose cytoplasm that part of a cell which sur- concentrations periodically rise and fall rounds the nucleus, composed of the cytosol in step with the cell cycle; they interact and various organelles and enclosed by a with and activate cyclin-dependent plasma membrane or cell surface membrane kinases (CDKs) which regulate the tran- cytoplasmic pertaining to the cytoplasm sition between stages of the cell cycle; cytosine a pyrimidine base of DNA and cyclin D1 plus CDK4 phosphorylates RNA, pairs with guanine pRB and releases the transcription factor, cytosine arabinoside an antimetabo- E2F, and histone deacetylase, permit- lite used in the treatment of acute myeloid ting the cell to progress from G1 to S (see leukaemia Fig. 15, p. 72) cytoskeleton a protein network within Cyclin D1 see BCL1; also known as the cytoplasm that gives a cell its shape, CCND1 composed of microfilaments, intermediate Cyclin D2 see CCND2 filaments and microtubules Cyclin D3 see CCND3 cytosol the gel-like mixture of water and cyclin-dependent kinase (CDK) a proteins that, together with the organelles group of negative regulators of cell which it contains, makes up the cyto- cycling, e.g. CDK4, CDK6 plasm of a cell cyclin-dependent kinase inhibitors cytospin a method of preparing a single (CDKI) two families of inhibitors of layer of cells for microscopic examination cyclin-dependent kinases, the Cip/Kip using a specialized centrifuge HAE-C 01/13/2005 05:10PM Page 86

86 cytotoxic drug

Figure 23 Cytotoxic T-cell function. The interactions between a cytotoxic T cell and its target. Activation of a cytotoxic T cell requires simultaneous signalling through the T-cell receptor and various other cell surface molecules. The antigen-presenting cell (APC), e.g. a virus infected autologous cell, processes an endogenous antigen to a peptide which is presented in a groove in the surface of an HLA class I molecule. It is recognized by the T-cell receptor–CD8 α β complex. CD54 (ICAM1) on the APC binds to CD11a/CD18 ( 2 2 integrin) on the T cell and CD58 binds to CD2. CD80 and CD86 on the APC are part of the innate immune system and are up-regulated when an APC recognizes a pathogen-associated molecule (e.g. lipopolysaccharide). They bind either to CD28, giving stimulatory signals, or to CD152 (CTLA4), giving inhibitory signals. CD40 binds to its ligand, CD154. Following binding and activation, the cytotoxic T cell inserts perforin into the membrane of the target cell, creating a pore through which granzymes enter, inducing apoptosis.

Antigen-presenting cell MHC Class CD54 CD80 CD86 CD40 CD58 I

CD28 CD28 CD11a/ TCR CD8 CD2 or or CD18 CD154 CD152 CD152

Cytotoxic T cell

peptide resulting from processing of antigen

cytotoxic drug a drug which is toxic to cytotoxic T cell a T cell that is able to cancer cells (and also to normal cells); the recognize antigens, in an HLA class I term was initially synonymous with context, and kill or damage cells bearing ‘alkylating agent’ but is now used in a these antigens; cytotoxic T cells are im- more general sense portant in defence against viral infections and in allograft rejection (Fig. 23) HAE-D 01/13/2005 05:10PM Page 87

δ chain (i) the δ globin chain which forms netrin-1 receptor, and is pro-apoptotic in

part of haemoglobin A2 (ii) the heavy the absence of this ligand; expression is chain of immunoglobulin D; two δ chains absent in most metastatic colorectal car- combine with two light chains (in a single cinomas, but is absent only in a minority molecule either κ or λ) to form a complete of non-metastatic cancers; loss of expres- immunoglobulin molecule (ii) part of the sion of DCC in colorectal carcinoma indi- γδ T-cell receptor, a surface membrane cates a poor outcome; point mutations structure in T lymphocytes which permits have been observed in colonic and oeso- antigen recognition phageal carcinoma; there is reduced ex- Da the abbreviation for dalton pression in about a third of cases of acute dacrocyte a teardrop shaped poikilocyte leukaemia and chronic granulocytic leuk- dactylitis a painful inflammation of the aemia, particularly in blast crisis fingers and toes, may be a caused by bone DDAVP 1-deamino-6-D-arginine vaso- infarction in sickle cell disease pressin, desmopressin acetate DAF a gene at 1q32 which encodes the gly- D-dimer a breakdown product of cross- cosylphosphatidyl inositol (GPI)-linked linked fibrin; its presence in increased decay accelerating factor; this protein concentration in the plasma is indicative carries the Cromer blood group antigens of local or disseminated intravascular dalteparin a low molecular weight coagulation heparin DDRT-PCR differential display PCR dalton (Da) the unit for measuring DDX10 a gene, DEAD/H BOX 10, gene molecular weight, the weight of a hydro- map locus 11q22-q23; encodes a widely gen atom expressed RNA helicase which contains danaparoid a heparinoid with anti- the evolutionarily conserved Asp-Glu- factor Xa activity Ala-Asp (DEAD) box sequence; con- dapsone an oxidant drug which often tributes to the NUP98-DDX10 gene in causes haemolysis inv(11)(p15q22) associated with de novo daunorubicin an anthracyclin used in and therapy-related acute myeloid leuk- the treatment of acute myeloid leukaemia aemia and myelodysplastic syndromes DBA-44 a monoclonal antibody which DEAD box a conserved motif (Asp-Glu- gives positive reactions with hairy cells, Ala-Asp—DEAD corresponds to the sin- with cells of most cases of splenic lym- gle letter amino acid code for this) found phoma with villous lymphocytes and in ATP-dependent proteins involved in with a subset of normal B cells RNA splicing and transport DCC a gene, Deleted in Colorectal decompression sickness see caisson Carcinoma also known as Colorectal disease Cancer-related chromosome sequence deep vein thrombosis (DVT) forma- 18, CRC18, and CRCR1, gene map locus tion of a clot within the deep veins of the 18q21.3; a candidate tumour suppressor leg, thigh or pelvis gene; encodes a protein with sequence degenerate oligonucleotide poly- similarity to N-CAM (CD56); acts as a merase chain reaction (DOP-PCR)

87 HAE-D 01/13/2005 05:10PM Page 88

88 DEK

a method of amplifying DNA using or more chromosomes, taking its name primers incorporating a short degenerate from the chromosome that contributes sequence, used for amplifying sequences the centromere non-specifically from sorted chromo- dermatitis inflammation of the skin somes, in order to develop whole chromo- dermatitis herpetiformis a chronic some paints skin disease with blistering, associated DEK a gene, gene map locus 6q23, encod- with gluten hypersensitivity and the small ing a ubiquitously expressed DNA-bind- bowel changes, and associated haemato- ing nuclear protein which is a component logical features, of coeliac disease of the so-called ‘exon–exon junction com- dermis the deeper part of the skin plex’; it contributes to the DEK-CAN desirudin a recombinant form of hirudin fusion gene in t(6;9)(q23;q34) associated desmin an antigen expressed by normal with acute myeloid leukaemia; the fusion muscle and rhabdomyosarcoma cells protein localizes to the nucleus and func- desmopressin acetate (DDAVP) 1- tions as a transcription factor deamino-6-D-arginine vasopressin, a vaso- del a cytogenetic abbreviation indicating pressin analogue that increases plasma a deletion concentration of von Willebrand factor deletion (i) deletion of part of a chromo- and factor VIII and also increases some, either part of the long arm or part fibrinolysis of the short arm (del) (ii) deletion of a DF2 an earlier name for the bacterium DNA sequence with the regions on either Capnocytophaga canimorsus which is trans- side being rejoined mitted by dog bites and can cause serious dementia loss of higher cerebral functions, infection in hyposplenic subjects

may result from vitamin B12 deficiency DH the Department of Health (United dendritic cell a specialized cell that pre- Kingdom) sents antigen to B cells DHFR the gene encoding dihydrofolate dendritic cell leukaemia an acute reductase, amplification or mutation of leukaemia of cells analogous to normal which can render leukaemic cells resistant dendritic cells to methotrexate de novo arising, apparently spontaneo- diabetes mellitus an acquired inability usly, without any preceding abnormality to control the blood sugar concentration, densitometer a laboratory instrument as a result of inadequate secretion of that uses a photoelectric cell to measure insulin by the pancreas differences in light transmission, can be Diamond–Blackfan syndrome consti- used to measure the concentration of tutional pure red cell aplasia; some cases, haemoglobin both inherited and apparently sporadic, deoxygenation the loss of oxygen from result from a mutation in the RPS19 the blood or from haemoglobin gene deoxyhaemoglobin haemoglobin diapedesis the passage of leucocytes which has given up oxygen to the tissues through a vessel wall, occurring without deoxyribonucleic acid (DNA) the major damage to the vessel constituent of the nucleus; a polynucleotide dic a cytogenetic abbreviation indicating strand that is able to replicate and which a dicentric chromosome codes for the majority of proteins synthe- DIC disseminated intravascular coagulation sized by the cell; the DNA molecule is dicentric chromosome (dic) an abnor- double-stranded, a double helix of two mal chromosome with two centromeres hydrogen-bonded complementary inter- Diego a minor blood group system, anti- twined polynucleotides gens being encoded by the AE1 (SLC4A1) der a cytogenetic abbreviation indicating gene at 17q21-q22 and expressed on a derivative chromosome membrane band 3 derivative chromosome (der) an differential count quantification of the abnormal chromosome derived from two different types of leucocyte in the circulat- HAE-D 01/13/2005 05:10PM Page 89

double blind 89

ing blood, expressed either as percentages DLI donor lymphocyte infusion (or donor or as the absolute count of each cell type leucocyte infusion) differential display PCR (DDRT-PCR) dm a cytogenetic abbreviation indicating a technique for the identification of dif- a double minute chromosome ferentially expressed genes using arbitrar- DNA deoxyribonucleic acid ily primed RT-PCR DNA ligase an enzyme that can repair differentiation (i) the process of com- breaks in a strand of DNA mitment to one lineage rather than another DNA methylation the attaching of (ii) maturation to cells typical of a certain methyl groups to DNA, with resultant lineage (iii) a stage in staining a blood film reduced expression of methylated genes that permits the differentiation of various DNA polymerase an enzyme that cat- leucocytes from each other alyses the assembly of DNA by adding diffuse evenly spread without any struc- nucleotides to the growing 3′ end of the ture; in relation to lymphoma is used molecule to indicate the absence of any follicular DO a gene on 12p encoding antigens of structure and also usually indicates that the Dombrock blood group system the marrow is heavily infiltrated by lym- Döhle body a weakly basophilic inclu- phoma cells (also referred to as a ‘packed sion within the cytoplasm of a neutrophil marrow’ pattern); in relation to chromatin composed of ribosomes structure indicates an immature cell domain a discrete region of a protein dimer a molecule composed of two pro- with a specific structure tein chains, which may be identical (homo- dominant inheritance a form of inher- dimer) or dissimilar (heterodimer) itance in which a single copy of a gene 2,3-diphosphoglycerate (2,3-DPG) causes an evident effect or determines the an intermediate in the glycolytic path- phenotype, the other allele being reces- way that decreases the oxygen affinity sive, see autosomal dominant of haemoglobin; 2,3-biphosphoglycerate dominant negative effect the effect of is now the preferred terminology (see a mutation in a gene which permits the Fig. 33, p. 113) gene to interfere with the function of a diploid having the normal complement normal allelic gene of 46 chromosomes Donath–Landsteiner antibody an anti- direct antiglobulin test a test for the body, often with anti-P specificity, cap- detection of immunoglobulin or comple- able of binding to red cells in the cold ment components on the surface of ery- and causing red cell lysis on rewarm- throcytes, also referred to as a direct ing; characteristic of paroxysmal cold Coombs’ test haemoglobinuria discordant lymphoma histologically donor an individual who donates blood different lymphoma at two anatomical or tissue for use by another sites, which may be clonally identical donor lymphocyte infusion (DLI) the disease-free survival survival without infusion of donor lymphocytes into a recurrence of a disease see also overall sur- recipient of a haemopoietic stem cell vival, event-free survival) transplant with the aim of recognizing disomic having the normal two copies of and destroying residual leukaemic cells an autosome in the recipient disomy the presence of the normal two DOP-PCR degenerate oligonucleotide poly- copies of an autosome merase chain reaction disseminated intravascular coagula- double blind a description of a random- tion (DIC) widespread deposition of ized controlled trial comparing two or fibrin within blood vessels more forms of treatment in which neither DKC1 a gene, gene map locus Xq28, the patient nor the doctor knows what mutation of which is responsible for treatment the patient is receiving until the X-linked dyskeratosis congenita trial is finished and a code is broken HAE-D 01/13/2005 05:10PM Page 90

90 double helix

double helix the tertiary structure of DNA duplication duplication of a gene or double minute chromosome (dm) DNA sequence encompassing several an abnormal chromosome with two genes or duplication of a segment of a chromatids and no centromere, i.e. an chromosome, the latter detectable by acentric fragment of a chromosome conventional cytogenetic analysis and down regulation a reduction in the designated ‘dup’ number of receptors of a specific type on Dutcher body an intranuclear inclusion a cell surface as the result of reduced in a plasma cell caused by invagination of expression of the relevant gene immunoglobulin-containing cytoplasm Down’s syndrome a congenital syn- into the nucleus drome of mental retardation with char- DVT deep vein thrombosis acteristic dysmorphic features as a dyscrasia a generic term used to refer to consequence of trisomy 21 (or of triplica- plasma cell and related neoplasms tion of a specific critical region of chro- (plasma cell dyscrasia) or, more generally, mosome 21); in neonates may cause to any disorder of the blood (blood polycythaemia and transient abnormal dyscrasia) myelopoiesis; in infants and older chil- dyserythropoiesis morphologically dren is associated with an increased incid- abnormal erythropoiesis ence of acute lymphoblastic leukaemia dysfibrinogenaemia presence of a dys- and acute myeloid leukaemia (particu- functional fibrinogen, usually an inher- larly acute megakaryoblastic leukaemia) ited, autosomal recessive abnormality doxorubicin an anthracycline antibiotic resulting from mutation in one of the used in the treatment of lymphoma and three fibrinogen genes, FGA, FGB and various carcinomas and sarcomas FGC at 4q28 2,3-DPG 2,3-diphosphoglycerate dysgranulopoiesis morphologically drumstick a nuclear appendage in abnormal granulopoiesis females that contains the inactive X dyskeratosis congenita an inherited chromosome syndrome characterized by abnormal dry tap jargon for an attempted bone skin pigmentation, dystrophic nails, marrow aspiration that yields nothing mucosal leukoplakia and aplastic dsDNA double-stranded DNA anaemia; inheritance may be X-linked Du see RHD recessive (the great majority of cases), Duffy a system of blood group antigens autosomal recessive or autosomal domin- (CD234); Duffy antigens are receptors ant; X-linked recessive cases can result for Plasmodium vivax and for several from mutation in the DKC1 gene and classes of pro-inflammatory cytokines autosomal dominant cases from muta- (see also FY ) tion in the hTR gene Duncan’s syndrome a sex-linked reces- dysmegakaryopoiesis dysplasia sive condition in which there is abnormal affecting megakaryocytes and platelets susceptibility to Epstein–Barr virus dysmorphism abnormal development infection, resulting from mutation of the leading to abnormal physical charact- SAP gene at Xq25, now generally eristics known as the X-linked lymphoprolifer- dysmyelopoiesis an alternative term ative syndrome for myelodysplasia duodenum the most proximal part of dysmyelopoietic syndromes an ear- the small intestine that connects the stom- lier designation of the myelodysplastic ach to the jejunum, the site of maximal syndromes iron absorption dysplasia morphologically abnormal dup a cytogenetic abbreviation indicat- cells or tissues ing a duplication HAE-E 01/13/2005 05:10PM Page 91

ε the epsilon gene and epsilon globin Figure 24 An echinocyte. chain, the latter being synthesized during An echinocyte, a cell covered with numerous short early embryonic life and forming part of regular spicules. haemoglobin Gower 1 and haemoglobin Gower 2 ε (epsilon) aminocaproate a cytochemical reaction which can be used to identify basophils E2A a gene, E-box 2A, correctly known as Transcription Factor 3, TCF3, also known as Immunoglobulin Transcrip- tion Factor 1, ITF1, E12 and E47; gene map locus 19p13.3, encodes two bHLH proteins, E12 and E47, by differential splicing; these proteins bind a motif in the immunoglobulin gene enhancer and are essential for B-cell development; E2A contributes to: • the E2A-PBX fusion gene in B-lineage acute lymphoblastic leukaemia associated with t(1;19)(q23;p13) • the E2A-HLF fusion gene in B-lineage acute lymphoblastic leukaemia associ- plexes actively repress transcription ated with t(17;19)(q21-22;p13) from promoters with E2F binding sites; There are at least two types of E2A-HLF deregulation of E2F1 activity is seen in rearrangements at the molecular level, a variety of neoplasms which result in different fusion proteins, EAP a gene, Epstein–Barr Associated both of which lead to arrested early B-cell Protein, correctly known as Ribosomal development Protein L22, RPL22; gene map locus E2F a gene, adenovirus E2 promoter 3q26; encodes a ribosomal protein; EAP binding transcription Factor 1, gene map contributes to the AML1-EAP fusion locus 20q11.2, encodes a widely expressed gene in acute myeloid leukaemia, the DNA-binding protein whose consensus myelodysplastic syndromes and blast binding sites are found in the promoters crisis of chronic granulocytic leukaemia of many genes encoding proteins involved associated with t(3;21)(q26;q22) in cell proliferation and speciﬁcally in EBV Epstein–Barr virus DNA synthesis; the archetypal member ecchymosis a large subcutaneous haem- of a family of related proteins essential orrhage, a form of purpura for the G1/S phase transition of the echinocyte an erythrocyte the surface of cell cycle; E2F proteins complex with which is covered by a large number of unphosphorylated RB1; RB1–E2F com- short regular spicules (Fig. 24)

91 HAE-E 01/13/2005 05:10PM Page 92

92 eclampsia

eclampsia pregnancy-associated hyper- nucleic acids by application to a mem- tension complicated by convulsions, may brane followed by exposure to a charge cause microangiopathic haemolytic anaemia gradient, e.g. serum protein electrophore- ectasia dilation, e.g. of a bone marrow sis or haemoglobin electrophoresis; the sinusoid separation of particles is determined EDTA ethylenediaminetetraacetic acid mainly by their size and their charge EEN a gene, Extra Eleven Nineteen leuk- elephantiasis non-pitting oedema, par- aemia fusion gene, correctly known as ticularly of the legs, as a consequence of SH3 domain, Grb2-Like, 1, SH3GL1; filariasis gene map locus; 19p13, encodes a ubi- ELISA enzyme-linked immunosorbent assay quitously expressed adapter molecule ELL a gene, Eleven nineteen Lysine-rich involved in intracellular signalling; a Leukaemia gene, also known as MEN; member of a recently described sub- gene map locus 19p13.1, encodes a ubiq- family of Src-homology-3 domain (SH3)- uitous transcription elongation factor containing proteins; EEN contributes which suppresses transient pauses by to the MLL-EEN fusion gene in acute RNA polymerase II during transcription; myeloid leukaemia associated with ELL contributes to the MLL-ELL fusion t(11;19)(q23;p13) gene in acute myeloid leukaemia associ- EGIL European Group for the Immuno- ated with t(11;19)(q23;p13.1) logical Characterization of Leukemias elliptocyte an elliptical erythrocyte ehrlichiosis disease caused by infection elliptocytosis presence of elliptical by Ehrlichia species erythrocytes ELA2 gene, gene map locus 19p13.3, elliptogenic giving rise to elliptocytosis encoding neutrophil elastase, mutations eluate a solution of a substance that is of which may cause both severe con- eluted genital neutropenia (some autosomal elution (i) removal of an absorbed sub- cases and the majority of sporadic cases) stance from a chromatography column and cyclical neutropenia (some autosomal (ii) removal of immunoglobulin from dominant and some sporadic cases) the surface membrane of an erythrocyte elastase an enzyme present in neutro- EMA epithelial membrane antigen phils and in other cells and tissues Embden–Meyerhof pathway see electrolyte a solute that forms ions in glycolytic pathway solution and conducts electricity embolism (i) the process of movement of electron a negatively charged elemen- a thrombus to another organ or site (ii) tary particle associated with the nucleus movement of a piece of tissue, such as of an atom bone marrow or atheromatous material, electronic issue the issuing of ABO- or extraneous material, such as air, compatible blood on the basis of a com- through the bloodstream puter programme, identification of suit- embolus (i) a blood clot that breaks free able units being by bar-code reading, and is transported by the flowing blood to applicable to patients with no atypical another organ or site (ii) any solid or antibodies and with two concordant cohesive material that moves through the results for ABO and Rh groups, one of bloodstream, usually causing obstruction which is on a current sample of arteries electron microscopy the production embryo the earliest stage of develop- of an image of a cell by using a beam of ment of the fertilized ovum, from implan- electrons, rather than light, to produce a tation up to about 8 weeks photographic image (see scanning elec- emesis vomiting tron microscopy, transmission electron emetic causing vomiting microscopy) emperipolesis active entry of haemo- electrophoresis separation of charged poietic cells into the surface-connected suspended particles such as proteins or canalicular system of megakaryocytes HAE-E 01/13/2005 05:10PM Page 93

epidermis 93

emphysema a chronic lung disease in lymphoblastic leukaemia associated with which there is destruction of air sacs or t(11;19)(q23;p13.3) alveoli leading to loss of oxygen-exchang- enolase an enzyme in the erythrocyte ing capacity; may lead to chronic hypoxia glycolytic pathway (see Fig. 33, p. 113) and therefore secondary polycythaemia enoxaparin a low molecular weight empirical based on experience without heparin the scientific basis necessarily being enzyme a protein produced by living understood cells that catalyses chemical reactions endemic constantly present in a com- enzyme-linked immunosorbent assay munity (ELISA) a method of quantifying an endocrine secreting a hormone that has antigen or an antibody by means of an an effect on distant tissues or organs enzyme-labelled immunoreactant and a endocytosis the process by which the solid-phase support surface membrane of a cell, usually with a eosin an orange dye, named for Eos—the specific particle bound to its receptor, is goddess of the dawn—used in Romanow- invaginated forming a vesicle containing sky stains of blood or bone marrow films the particle and some extracellular fluid; and in haematoxylin and eosin (H & E) phagocytosis is a specialized form of stains of histological sections endocytosis in which larger particles are eosinopenia a reduction in the engulfed eosinophil count endogenous coming from within eosinophil a granulocyte with aci- endonuclease an enzyme that cleaves dophilic granules which stain orange with DNA or RNA within the strands rather the acid stain, eosin than at the ends eosinophilia an increased eosinophil endoplasmic reticulum a cytoplasmic count organelle composed of a fluid-filled eosinophilic (i) showing increased up- membrane system that is concerned with take of eosin by a cell or tissue component synthesis and transport of proteins and (ii) pertaining to the eosinophil lineage lipids; composed of the rough and the eosinophilic granuloma a form of smooth endoplasmic reticulum Langerhans cell histiocytosis in which the endosteal cells cells lining the inner sur- lesions are infiltrated by eosinophils face of bone, osteoblasts and osteoclasts eosinophilic leukaemia a leukaemia endosteum the inner lining of bone with prominent eosinophilic differentia- endothelial cells cells lining blood and tion lymphatic vessels eotaxin a chemokine (of the CC family), endotoxic shock an acute illness with which is produced by eosinophils, hypotension mediated by endotoxin some epithelial cells, lymphocytes and endotoxin a toxin contained in the walls macrophages, and is a powerful chemoat- of certain bacteria tractant for eosinophils enhancer a DNA sequence that EPB41 a gene, gene map locus 1p33-34.2, influences the promoter of a nearby gene encoding protein 4.1 of the red cell mem- to increase or decrease the initiation of brane (see Fig. 33, p. 113); mutation may transcription; an enhancer acts on a gene result in hereditary elliptocytosis in cis and may be sited upstream, down- EPB42 a gene, gene map locus 15q15, stream or within a gene encoding pallidin, also known as protein ENL a gene, Eleven Nineteen Leukaemia 4.2 (see Fig. 33, p. 113), a component of gene also known as Mixed Lineage the red cell membrane; mutations can Leukaemia, Translocated to, 1, MLLT1; result in hereditary spherocytosis gene map locus 19p13.3, encodes a epidemic occurring in episodic out- nuclear transactivating protein; ENL breaks contributes to the MLL-ENL fusion gene epidermis the squamous cells forming in acute myeloid leukaemia and acute the most superficial layer of the skin HAE-E 01/13/2005 05:10PM Page 94

94 epidermotropism

epidermotropism having a tendency to Family; amplification of this gene has infiltrate the epidermis been reported in a case of myelodysplas- epinephrine adrenaline, the main hor- tic syndrome transforming to acute mone secreted by the adrenal medulla; a myeloid leukaemia; expression has been platelet agonist reported in some cases of B-lineage acute epistaxis bleeding from the nose lymphoblastic leukaemia; overexpression epithelial cell the surface cell of skin or of ERBB2 has been reported in prostate mucous membrane cancer and in 25–30% of breast cancer, epithelial membrane antigen (EMA) where it confers Taxol resistance, increas- an antigen expressed by cells of epithelial ing the aggressiveness of the tumour; origin and by cells of anaplastic large cell however a recombinant monoclonal anti- lymphoma body against ERBB2 (trastuxumab) epithelioid cell an altered macrophage increases the clinical benefit of first-line with abundant eosinophilic cytoplasm chemotherapy in metastatic breast cancer epithelioid granuloma a cohesive that overexpresses the protein collection of altered macrophages, ERFC E-rosette forming cell referred to as epithelioid cells, with or ERG a gene, Early Response Gene, also without other cells; this term covers all known as v-ets, avian erythroblastosis, granulomas with the exception of lipid avian E26 oncogene-Related Gene, granulomas ERG1 and ERG2; gene map locus epithelium the surface covering of the 21q22.3; encodes an ETS family tran- body and of the gastrointestinal, respirat- scription factor which interacts in in ory and genitourinary tracts vitro assays with SAP18, a transcriptional epitope an antigenic determinant, part repressor in haemopoietic cells; ERG of an antigen which can be specifically contributes to the FUS-ERG fusion gene recognized by a cell or antibody, e.g. by in acute myeloid leukaemia associated binding to a receptor on a B or T lympho- with t(16;21)(p11;q22) cyte or by binding to a highly specific E-rosette forming cell (ERFC) a T cell, monoclonal antibody defined by its ability to form rosettes with EPO erythropoietin sheep red blood cells; such cells express EPOR the gene at 7q11-22, encoding the CD2 erythropoietin receptor, mutated in some erythema redness of the skin or mucous types of familial polycythaemia membrane caused by vascular dilation Epstein–Barr virus (EBV) a herpesvirus erythremic myelosis a neoplasm which causes infectious mononucleosis characterized by increased and abnormal and is also one of the aetiological factors erythropoiesis in a number of lymphomas including erythroblast a nucleated red cell precur- endemic Burkitt’s lymphoma sor Epstein’s syndrome an inherited syn- erythroblastic pertaining to erythro- drome of renal failure, sensorineural blasts deafness and thrombocytopenia resulting erythroblastic island a cluster of ery- from a mutation in the non-muscle throblasts surrounding a central myosin heavy chain 9 gene (NMMHC-A macrophage in the bone marrow or MYH9) at 22q11-13 (or 22q12.3- erythroblastosis fetalis an alternative q13.2); a variant of Alport’s syndrome designation of haemolytic disease of the ERBB2 a gene, avian Erythroblastic newborn Leukaemia viral oncogene homologue 2, erythrocyte a red cell, a non-nucleated also known as Herstatin (Her2), Neu peripheral blood cell containing and Tyrosine Kinase-type cell surface haemoglobin and having oxygen trans- Receptor, TKR1; gene map locus port as its major function 17q21.1; encodes an orphan receptor erythrocyte sedimentation rate (ESR) tyrosine kinase of the EGF Receptor the rate at which erythrocytes sediment in HAE-E 01/13/2005 05:10PM Page 95

ethylenediaminetetraacetic acid (EDTA) 95

Figure 25 Erythropoiesis and granulopoiesis. A diagrammatic representation of the various stages of erythropoiesis and granulopoiesis.

Myeloblast Promyelocyte Myelocyte Metamyelocyte Band Neutrophil cell Common erythroid/granulocytic precursor

Proerythroblast Early Intermediate Late Polychromatic Mature erythroblast erythroblast erythroblast erythrocyte erythrocyte

anticoagulated blood; more precisely, the erythropoietin receptor a receptor for number of millimetres which red cells erythropoietin, which is abundant on red have sedimented after one hour cell precursors, encoded by the EPOR gene erythrocytosis an increased red cell ESR erythrocyte sedimentation rate count, haemoglobin and haemato- essential primary, having no recognized crit; the term is synonymous with external cause ‘polycythaemia’ essential cryoglobulinaemia cryo- erythroderma an abnormality of the globulinaemia occurring as a manifesta- skin associated with redness, not due to tion of a plasma cell neoplasm which is simple vasodilation otherwise occult erythroid pertaining to erythroblasts or essential erythrocytosis polycyth- erythropoiesis aemia for which no cause can be found; erythroleukaemia acute myeloid leu- many cases represent an early stage of kaemia with prominent erythroid dif- polycythaemia rubra vera ferentiation; as deﬁned by the FAB essential thrombocythaemia a myelo- group, erythroleukaemia or M6 AML proliferative disorder with thrombocy- is AML with more than 50% of bone tosis without coexisting polycythaemia marrow nucleated cells being erythroid ester a chemical compound formed by (see Tables 3 and 4, pp. 7 and 8) bonding of an alcohol and one or more erythrophagocytosis phagocytosis of organic acids; fats are esters erythrocytes esterase an enzyme catalysing the erythropoiesis the process by which hydrolysis of an ester erythroid progenitors gives rise to mature ET essential thrombocythaemia erythrocytes or red cells (Fig. 25) ethnic origin deriving from a group erythropoietin (EPO) a hormone, with a common culture and sharing secreted mainly by the kidney, which pro- genetic characteristics motes erythropoiesis, available in recom- ethylenediaminetetraacetic acid binant form for therapeutic use (EDTA) a chelator of bivalent cations HAE-E 01/13/2005 05:10PM Page 96

96 ETO

which is used, in the form of its sodium or and repression functions; it is essential for potassium salt, as an anticoagulant for yolk sac angiogenesis and adult haemo- blood samples for a haemoglobin estima- poiesis; ETV6 has been rearranged in tion and blood count at least 41 different translocations and ETO a gene, Eight Twenty One, also many of the partner genes have been known as Core-Binding Factor (see Fig. cloned; involvement of the PNT domain 29, p.107), Alpha subunit 2, Translocated of ETV6 in these fusion genes permits to, 1 (CBFA2T1) and Myeloid Trans- oligomerization of any resulting chi- location Gene on 8q22, MTG8; gene map maeric proteins; ETV6: locus 8q22; named for the chromosomes • contributed to an ETV6-ARNT fusion involved in the t(8;21)(q22;q22) translo- gene in a case of M2 acute myeloid leuk- cation in which part of this gene is fused aemia associated with t(1;12)(q21;p13) to part of the AML1 gene to form AML1- • contributed to the ETV6-ARG ETO; homologous to the Drosophila gene (ABL2) fusion gene in t(1;12)(q25;p13), nervy; encodes a non-DNA-binding nuclear occurring as a second event in a case of protein normally expressed in gut, testes M3 acute myeloid leukaemia associated and central nervous system which is with t(15;17) involved in the recruitment of histone • contributed to the ETV6-MDS1/EVI1 deacetylases to the transcriptional complex in a case of chronic myeloid leukaemia etoposide an anticancer drug, which is a associated with t(3;12)(q26;p13) topoisomerase-II interactive agent, used • contributes to a BTL/CHIC2-ETV6 in treating lymphoma fusion gene in acute myeloid leukaemia ETS a family of transcription factor associated with t(4;12)(q11-12;p13) regulators related to the product of v-ets • contributes to an ETV6-ACS2 fusion (E26-Transformation Speciﬁc), a viral on- gene in myelodysplastic syndrome and cogene encoded by the avian erythroblas- acute myeloid leukaemia associated with tosis virus; ETS proteins are characterized t(5;12)(q31;p13) by a conserved winged helix-turn-helix • contributes to the ETV6-PDGFRB DNA-binding domain (ETS domain) fusion gene in chronic myelomonocytic which binds DNA sequences centred over leukaemia with eosinophilia associated a core motif (EBS: ETS binding site); a with t(5;12)(q33;p13) subset of ETS proteins also carry an • contributed to an ETV6-STL fusion amino-terminal pointed (PNT) domain gene in a B-lineage acute lymphoblastic which permits interactions with distinct leukaemia cell line with t(6;12)(q23;p13) protein partners, thereby establishing • contributed to an ETV6-AF7p15 fusion unique biological functions within the gene in a patient with acute myeloid leuk- family; ETS proteins are downstream aemia associated with t(7;12)(p15;p13) effectors of RAS-MAPK signalling • contributed to an HLXB9-ETV6 fusion cascades—most ETS transcription fac- gene in infant acute myeloid leukaemia tors are phosphorylated and activated associated with t(7;12)(q36;p13) by speciﬁc MAP kinases, however some, • contributes to the ETV6-JAK2 fusion e.g. ERG, are inhibitory; they regulate gene is rare cases of acute lympho- varied physiological and pathophysiolo- blastic leukaemia or atypical chronic gical processes such as haemopoiesis, myeloid leukaemia associated with either apoptosis and tumorigenesis t(9;12)(p24;p13) or with a complex chro- ETV6 a gene, Ets Variant gene 6, homolo- mosomal rearrangement with the same gous with v-ets, gene map locus 12p13, breakpoints also known as TEL, encodes a transcrip- • contributed to an ETV6-SYK fusion tion regulator; it belongs to the ETS fam- gene in a patient with a myelodysplastic– ily and has a pointed (PNT) domain and a myeloproliferative syndrome associated 3′ ETS DNA binding domain; ETV6 is with t(9;12)(q22;p12) ubiquitously expressed and exhibits con- • contributes to the ETV6-ABL fusion text-dependent transcriptional activation gene in rare cases of acute lymphoblas- HAE-E 01/13/2005 05:10PM Page 97

ex vivo 97

tic leukaemia, acute myeloid leukaemia • contributes to the fusion gene, AML1- and chronic myeloid leukaemia associ- MDS1-EVI1, in acute myeloid leukaemia ated with t(9;12)(q34;p13) or a variant associated with t(3;21)(q26;q23) translocation • contributes to the ETV6-EVI1 fusion • contributes to an ETV6-CDX2 fusion gene in acute myeloid leukaemia associ- gene in acute myeloid leukaemia associated with t(3;12)(q26;p13) ated with t(12;13)(p13;q12) • is involved in the translocations • contributes to an ETV6-TRKC fusion t(2;3)(p13;q26) gene in acute myeloid leukaemia and t(2;3)(q23;p26) in familial fibrosarcoma associated with t(3;17)(q26;q22) t(12;15)(p13;q25); the acute myeloid exfoliative tending to lose layers of cells leukaemia and fibrosarcoma mutations exocrine pertaining to secretion of a differ at a molecular level substance which has an effect outside • contributes to the ETV6-AML1 the tissues of the body, e.g. within the fusion gene in the 30% of cases of acute gastrointestinal tract or on the skin lymphoblastic leukaemia that are asso- exocytosis the process in which a sec- ciated with a cryptic t(12;21)(p13;q22); retory vesicle produced in the Golgi there is generally loss of the normal complex moves to the surface of the cell, ETV6 allele suggesting that loss of fuses with the surface membrane and ETV6 function may contribute to discharges its contents oncogenesis exogenous coming from outside • contributes to the MN1-ETV6 fusion exon a part of a gene which is repres- gene in acute myeloid leukaemia associ- ented in mature messenger RNA; most ated with t(12;22)(p13;q11) genes are composed of exons and non- • contributed to PAX5-ETV6 fusion transcribed introns (see Fig. 32, p. 111) gene in a case of acute lymphoblastic exonuclease an enzyme that breaks leukaemia down DNA or RNA from the ends of the euchromatin diffuse or non-condensed strands transcriptionally active chromatin extramedullary occurring outside the eukaryocyte a cell with a nucleus bone marrow European Group for the extramedullary haemopoiesis haemo- Immunological Characterization of poiesis occurring outside the bone Leukemias (EGIL) a cooperative marrow, usually in the liver and spleen group that published guidelines on extramedullary myeloma extra- immunophenotyping medullary plasmacytoma, a plasma Evans’ syndrome autoimmune haemo- cell tumour occurring outside the bone lytic anaemia plus autoimmune thrombo- marrow cytopenic purpura extrinsic something which originates event-free survival survival without outside rather than being an essential disease relapse or the need to change to part; the extrinsic pathway of coagula- alternative treatment (see also, disease- tion involves activation of factor VII by free survival, overall survival) tissue factor with subsequent activation EVI1 a gene, Ecotropic Viral Integration of factors X and II and conversion of site 1, gene map locus 3q26; encodes a fibrinogen to fibrin; in contrast to the zinc finger nuclear protein which can intrinsic pathway, the circulating blood repress transcription and recruits histone does not contain all the factors necessary deacetylases; EVI1: for the pathway (see Fig. 17, p. 77) • is 5′ truncated and dysregulated by extrinsic pathway inhibitor see tissue proximity to the enhancer elements of the factor pathway inhibitor ribophorin 1 gene and forms a GR6-EVI1 ex vivo a process which is detected in fusion gene in acute myeloid leukaemia cells or tissues that have been removed associated with inv(3)(q21q26) and from the body; the term should be con- t(3;3)(q21;q26) trasted with in vivo and in vitro HAE-F 01/13/2005 05:11PM Page 98

F2 the gene at 11p11-q12 that encodes F13B the gene at 1q31-q32.1 that encodes prothrombin (factor II), a coagulation the B subunit of factor XIII factor in both the intrinsic and extrinsic Fab that part of an immunoglobulin pathways, mutation of which can molecule that is capable of binding to lead to prothrombin deficiency or antigens (see Fig. 48, p. 139) thrombophilia FAB pertaining to the French–American– F5 the gene at 1q23 that encodes factor British Cooperative Group and their V, a coagulation factor in both the in- classifications (see Table 3, p. 7) trinsic and extrinsic pathways, mutation Fabry’s disease angiokeratosis corporis of which can lead to autosomal recessive diffusum, an inherited disease in which factor V deficiency or to factor V Leiden, phospholipids are stored in many parts of associated with thrombophilia the body, particularly in blood vessels F7 the gene at 13q34 that encodes factor FACS fluorescence-activated cell sorter VII, a coagulation factor of the extrinsic or sorting pathway, mutation of which can lead to factitious false, not genuine, artefactual factor VII deficiency (of a laboratory test result), sometimes F8C the gene at Xq28 that encodes factor deliberately caused by an individual to VIII, a coagulation factor in the intrinsic simulate illness pathway, mutation of which can lead to factor I (roman numeral) fibrinogen, a haemophilia A; about a third of mutations plasma protein that is converted to fibrin are new sporadic mutations by the action of thrombin thus leading to F9 the gene at Xq27.1-q27.2 that encodes clot formation; the Aα, Bβ and γ chains factor IX, a coagulation factor in the are encoded respectively by the FGA, intrinsic pathway, mutation of which can FGB and FGG genes; (not to be confused lead to factor IX deficiency with factor I [upper case i] of the comple- F10 the gene at 13q34 that encodes factor ment system) X, a coagulation factor in both the intrin- factor II prothrombin, a vitamin K- sic and extrinsic pathways, mutation of dependent coagulation factor encoded which can lead to factor X deficiency by the F2 gene; it is converted to thrombin F11 the gene at 4q35 that encodes factor by the action of activated factor X, in XI, a coagulation factor of the intrinsic the presence of calcium, phospholipid pathway; mutations of this gene, which and activated factor V (see Fig. 17, p. are prevalent among Ashkenazi Jews, 77) can lead to factor XI deficiency in both factor II: G20210A a variant form of homozygotes and heterozygotes factor II with a point mutation in the 3′ F12 the gene at 5q33-qter that encodes untranslated region, associated with factor XII, the first factor of the intrinsic increased plasma concentration of factor pathway of coagulation, mutation of II and some increase in risk of thrombo- which can lead to factor XII deficiency sis, present in 1–1.5% of some Caucasian F13A1 the gene at 6p25-p24 that encodes populations the A subunit of factor XIII factor IIa activated factor II, thrombin

98 HAE-F 01/13/2005 05:11PM Page 99

factor H 99

factor V a coagulation factor in the com- in the plasma; it facilitates the activation mon pathway which also contributes to of factor X by activated factor IX (see physiological anticoagulation; it is encoded Figs 17 and 18, pp. 77 and 78) by the F5 gene; activated factor V, factor factor VIIIa activated factor VIII Va, is a cofactor in the conversion of factor IX Christmas factor, a vitamin prothrombin to thrombin by factor Xa; K-dependent factor in the intrinsic path- non-activated factor V is a cofactor with way encoded by the F9 gene (see Figs 17 protein S in the inactivation of factor Va and 18, pp. 77 and 78) and factor VIIIa by activated protein C factor IXa activated factor IX (see Figs 17 and 56, pp. 77 and 170) factor X a vitamin K-dependent factor factor Va activated factor V, a cofactor in the common coagulation pathway; in the conversion of prothrombin to factor X is activated both by factor VIIa thrombin by factor Xa (see Fig. 17, p. 77) and by factor IXa (in the presence of fac- factor V and factor VIII deficiency an tor VIIIa in a calcium- and phospholipid- inherited, autosomal recessive, deficiency dependent reaction); in turn it activates of factors V and VIII resulting from a prothrombin to thrombin, by a calcium- mutation in the LMAN1 gene and phospholipid-dependent reaction in factor V Leiden a variant form of factor the presence of factor Va (see Figs 17 and V, also known as factor VR506Q and 18, pp. 77 and 78) factor VQ506, resulting from a 1691G→Α factor Xa activated factor X mutation in the F5 gene; factor V Leiden factor XI a factor in the intrinsic pathway, has a prevalence of 3–15% in different encoded by the F11 gene; it is activated Caucasian populations; the mutation by factor XIIa in vitro and by thrombin leads to an alteration of protein structure in vivo and in turn it activates factor IX at the point where factor V is cleaved (see Figs 17 and 18, pp. 77 and 78) by activated protein C and this renders factor XIa activated factor XI factor V resistant to inactivation by factor XII Hageman factor, the first fac- activated protein C and also less effect- tor in the intrinsic pathway, encoded by ive as a cofactor for the inactivation of the F12 gene; after contact activation in factor VIIIa by activated protein C vitro, it leads to activation of factor XI; (see Fig. 56, p. 170); there is mild throm- deficiency causes marked abnormality of bophilia and probably increased suscepti- in vitro tests of the intrinsic pathway but bility to thrombotic microangiopathy in vivo is not associated with any haemor- factor VII a vitamin K-dependent coagu- rhagic disorder (see Fig. 17, p. 77) lation factor, the first factor in the ex- factor XIIa activated factor XII trinsic pathway of coagulation, which on factor XIII a factor composed of two A vascular injury forms a 1:1 stoichiometric subunits and two B subunits, encoded by complex with tissue factor exposed on the F13A1 and F13B respectively that, when endothelial cell; complexing of factor VII activated, causes stable cross-linking of to tissue factor leads to its activation; fibrin (see Fig. 18, p. 78) activated factor VII initiates the extrinsic factor XIIIa activated factor XIII pathway of coagulation and also activ- factor B a protein in the alternative ates factor IX of the intrinsic pathway complement pathway (see Fig. 20, p. 81) (see Fig. 18, p. 78) factor D a protein in the alternative factor VIIa activated factor VII, avail- complement pathway (see Fig. 20, p. 81) able as a recombinant coagulation factor factor H an glycoprotein encoded by a factor VIII anti-haemophiliac globulin, a gene at 1q32 which inhibits complement coagulation factor in the intrinsic pathway activation; factor H competes with factor encoded by the F8C gene, synthesized in B for C3b and acts as a cofactor for factor the liver but requires von Willebrand’s I in the inactivation of C3b (see Fig. 20, factor (synthesized in megakaryocytes p. 81); homozygous deficiency can be and endothelial cells) for normal stability associated with familial or sporadic HAE-F 01/13/2005 05:11PM Page 100

100 factor I (upper case i)

relapsing haemolytic uraemic syndrome FANCG a gene at 9p13, mutation of and membranous glomerulonephritis which explains about 10% of cases of factor I (upper case i) an inhibitory Fanconi’s anaemia protein in the complement system; homo- Fanconi’s anaemia a recessively in- zygous deficiency can be associated with herited, clinically and genetically hetero- haemolytic uraemic syndrome and mem- geneous chromosomal fragility syndrome, branous glomerulonephritis characterized by multiple congenital abnor- faggot cell a cell containing bundles malities, aplastic anaemia with onset of Auer rods, a feature of hypergranular usually in childhood and a predisposition promyelocytic leukaemia and its hypo- to acute myeloid leukaemia and other granular/microgranular variant tumours falciparum malaria malaria caused by FAS a gene, Tumour Necrosis Fac- Plasmodium falciparum tor Receptor Superfamily, member 6, false negative a negative result that TNFRSF6, CD95, gene map locus 10q24.1, should have been positive encodes a transmembrane protein belong- false positive a positive result that should ing to the TNF family that mediates apo- have been negative ptosis when trimerized by cross-linking familial occurring in families, by implica- to Fas ligand; FAS is mutated in about tion inherited 10% of cases of multiple myeloma and familial cold urticaria an autosomal in about 10% of cases of non-Hodgkin’s dominant disorder resulting from a muta- lymphoma, particularly MALT-type tion in the CIAS1 gene, resulting in a non-Hodgkin’s lymphoma and extra- periodic cold-induced non-pruritic non- nodal B-lineage diffuse large cell urticarial rash associated with neutrophilia lymphoma familial haemophagocytic lympho- FBP17 a gene, Formin Binding Protein histiocytosis (FHL) a familial syn- 17, centromeric to 9q34; encodes a drome, probably basically an immune ubiquitously expressed protein which is deficiency syndrome, characterized by believed to interact with SNX proteins, haemophagocytic syndromes occurring involved in EGF receptor trafficking; in childhood and often being fatal; two FBP17 contributed to a MLL-FBP17 fusion genetic mechanisms have been deter- gene in an infant with M4 acute myeloid mined, linked to 10q21-22 in FHL1 and leukaemia linked to 9q21.3-22 (PERF1 gene) in Fc the constant part of an immunoglo- FHL2. bulin molecule that determines antibody familial Mediterranean fever an auto- class (G, A, M, E, D) and is responsible somal recessive disease, resulting from for fixation of complement and interac- mutation in the MEFV gene, character- tion with effector cells such as granulo- ized by periodic fever and serositis cytes, monocytes, mast cells and killer FAN see CEP110 cells (see Fig. 48, p. 139) FANCA a gene at 16q24.3, mutation of Fc receptor a receptor for the Fc part of which explains 65–70% of cases of an immunoglobulin molecule (see FcγR, Fanconi’s anaemia FcεR) FANCC a gene at 9q22.3, mutation of FcεR receptor for the Fc part of the which explains 10–15% of cases of immunoglobulin E molecule Fanconi’s anaemia FcγR receptor for the Fc part of the FANCD2 a cloned gene that causes some immunoglobulin G molecule: FcγRI, high cases of Fanconi’s anaemia affinity receptor on monocytes; FcγRII, FANCE a cloned gene that causes some lower affinity receptor on neutrophils, cases of Fanconi’s anaemia monocytes, eosinophils, platelets and B FANCF a gene at 11p15, mutation of cells; FcγRIII, low affinity receptor on which explains <2% of cases of Fanconi’s macrophages, neutrophils, eosinophils anaemia and NK cells HAE-F 01/13/2005 05:11PM Page 101

FHIT 101

FCGRIIB a gene, low affinity Fc Gamma FGFR1 a gene, Fibroblast Growth Factor Receptor IIB, CD32, gene map locus Receptor 1, gene map locus 8p11.2-p11.1, 1q22; involved in the t(1;22)(q22;q11) re- encodes a receptor tyrosine kinase; con- arrangement found in less than 1% of cases tributes to: of follicular lymphoma and associated •a ZNF198-FGFR1 fusion gene in a with transformation to high grade disease syndrome of chronic myelomonocytic FDPs fibrin degradation products leukaemia with eosinophilia/T-lineage Fechtner’s syndrome an inherited lymphoblastic lymphoma, sometimes syndrome characterized by renal failure, referred to as the 8p11 syndrome or the sensorineural deafness, thrombocytope- stem cell leukaemia–lymphoma syndrome, nia and neutrophil inclusions that re- associated with t(8;13)(p11;q11-12) semble Döhle bodies; a variant of Alport’s • the FOP-FGFR1 fusion gene in a syndrome and Epstein’s syndrome result- similar disorder associated with ing from a mutation in the non-muscle t(6;8)(q27;p11) myosin heavy chain 9 gene (NMMHC-A • the CEP110-FGFR1 fusion gene in or MYH9) at 22q11-13 (or 22q12.3- t(8;9)(p11-12;q33) associated with the q13.2) same syndrome Felty’s syndrome hypersplenism causing • the BCR-FGFR1 fusion gene in asso- pancytopenia in a patient with rheuma- ciation with chronic myeloid leukaemia toid arthritis; there may be an underlying and t(8;22)(p11;q11) large granular lymphocyte leukaemia FGFR1 was also found to be rearranged ferric pertaining to trivalent iron (Fe3+) in a case of chronic myeloid leukaemia ferritin a complex of iron and a protein, associated with systemic mastocytosis apoferritin; ferritin is present in the cyto- FGFR3 a gene, Fibroblast Growth Factor plasm of erythroblasts; in macrophages Receptor 3, gene map locus 4p16.3; it is converted into haemosiderin, the encodes a receptor tyrosine kinase which principal storage form of iron; small is dysregulated, by proximity to the IGH amounts are present in the plasma, and Cα enhancer on chromosome 14, in measurement of serum ‘ferritin’ (actually t(4;14)(p16.3;q32), a cryptic transloca- apoferritin) permits assessment of body tion associated with multiple myeloma iron stores FGG a gene at 4q28 encoding the γ chain ferrous pertaining to bivalent iron (Fe2+), of fibrinogen, mutation of which can lead the form of iron that is incorporated into to dysfibrinogenaemia protoporphyrin IX by ferrochelatase (see FHIT a gene, Fragile Histidine Triad gene, Fig. 34, p. 116) also known as AP3A hydrolase, gene ferrous sulphate an iron compound map locus 3p14.2; the FRA 3B fragile used to treat iron deficiency anaemia site; the gene is composed of 10 exons dis- fertilization the fusion of a spermato- tributed over at least 500 kb, and encodes zoon with an ovum to form a zygote a widely expressed enzyme involved in the fetal pertaining to the fetus regulation of DNA replication; deletions fetal haemoglobin haemoglobin F and structural rearrangements in FRA fetus the unborn offspring after it has at- 3B have been observed in many epithelial tained the particular form of the species, malignancies; loss of FHIT function is e.g. in man the unborn offspring beyond important in the development and/or 8 weeks from fertilization progression of head and neck squamous FFP fresh frozen plasma cell cancers, and cervical, oesophageal FGA a gene at 4q28 encoding the Aα and lung cancers; FHIT expression is chain of fibrinogen, mutation of which reduced in a majority of cases of acute can lead to dysfibrinogenaemia lymphoblastic leukaemia and in a signi- FGB a gene at 4q28 encoding the Bβ chain ficant proportion of cases of chronic of fibrinogen, mutation of which can lead myeloid leukaemia, the significance of to dysfibrinogenaemia this being unclear HAE-F 01/13/2005 05:11PM Page 102

102 FHL

Figure 26 The fibrinogen molecule. A diagrammatic representation of the fibrinogen molecule showing the Aα, Bβ and γ chains, the sites of cleavage by thrombin to produce fibrinopeptides A and B (black) and the sites of cleavage by plasmin.

NH terminal α T T α A Aα Aα A Bβ Bβ TT P P Bβ P P γγ P P Bβ P P

COOH COOH terminal γ γ terminal

T Thrombin cleavage site Aα Aα chains (fibrinopeptides A and B shown in black) Bβ Bβ chains P Plasmin cleavage site γγ Disulphide links chains

FHL familial haemophagocytic lymphohis- fibroblast the cell that is responsible tiocytosis for synthesis and deposition of collagen; fibre FISH a FISH technique using very small numbers of fibroblasts are present elongated genomic DNA in the bone marrow fibrin a fibrillar protein, the formation of fibrosis the replacement of normal tissue, which is the basis of blood coagulation; e.g. the bone marrow, by fibroblasts and fibrin is formed by polymerization and collagen; the term ‘fibrosis’ may also be cross-linking of fibrin monomers, which used to refer to reticulin deposition but a are produced by the action of thrombin on distinction should be drawn between reti- fibrinogen culin deposition and collagen deposition fibrin degradation products (FDPs) filariasis a disease resulting from infec- breakdown products of fibrin which are tion by filarial parasites such as Loa loa, present in the plasma in increased con- Wuchereria bancrofti and Brugia malayi centration in the presence of extensive or filgrastim recombinant granulocyte disseminated intravascular coagulation or colony-stimulating factor increased fibrinolysis; D-dimer is a specific FIM a gene, Fused In Myeloproliferative fibrin degradation product disorders, see ZNF198 fibrinogen a soluble plasma protein FISH fluorescence in situ hybridization (Fig. 26) that is converted, by the action fixation (i) the process by which cells are of thrombin, into fibrin monomers, which killed and tissues and cells are preserved polymerize and are cross-linked to form by exposure to chemicals such as ethanol, a stable, insoluble fibrin polymer, thus methanol, acetone or formalin (ii) the leading to blood clotting: also known as process by which complement components factor I are bound to immunoglobulin that has fibrinolysis the process by which plas- already formed a complex with antigen min breaks down fibrin (Fig. 27) FKHR a gene, Forkhead box O1A, fibrinolytic pertaining to fibrinolysis FOXO1A, gene map locus 13q14.1; HAE-F 01/13/2005 05:11PM Page 103

FL 103

Figure 27 The fibrinolytic pathways. Major pathways are shown by a solid arrow and minor pathways by a dotted arrow. Two lines across an arrow indicate a negative effect, either inhibition or destruction. Dashed crossed lines indicate proteolysis with resultant reduction inactivity of the target protein. Thrombin activation and fibrin deposition lead to activation of fibrinolysis. Fibrin binds plasminogen and plasminogen is converted to plasmin by tissue plasminogen activator (tPA) released from activated endothelial cells. Plasmin breaks down fibrin and the fact that plasmin is formed from plasminogen bound to fibrin means that, normally, fibrinolysis is preferentially focused in the area of fibrin deposition. However if there is excess free plasmin, fibrinogen, factor Va and factor VIIIa can all α α α α be degraded. 2 antiplasmin ( 2AP) and 2 macroglobulin ( 2M) inhibit the action of plasmin, particularly circulating plasmin. Plasminogen activator inhibitors 1 and 2 (PAI1 and PAI2) inhibit the action of tPA, thus reducing fibrinolysis. Thrombin production also leads to activation of protein C which, to some extent, breaks down PAI1, thus enhancing fibrinolysis. However, thrombin also activates thrombin-activatable fibrinolysis inhibitor (TAFI), which inhibits the action of plasmin on fibrin. There is thus a delicately balanced system of positive and negative controls of fibrinolysis.

IX IXa VIIIa Phl Ca2+

X Xa Va Phl Ca2+ PC thrombin– II IIa thrombomodulin complex

APC PAI

Fibrinogen Fibrin Plasminogen

tPA

TAFI Plasmin XIIa Kallikrein

FDPs α 2M α 2AP

Major pathway Negative effect Minor pathway

encodes a forkhead domain transcrip- FKHR fusion genes, in t(2;13)(q35;q14) tion factor that is negatively regulated by and t(1;13)(p36;q14) respectively, in alve- protein kinase B signalling (see AKT) and olar rhabdomyosarcoma is essential for the completion of mitosis; FL a gene at 13q12-13 that encodes contributes to the PAX3-FKHR and PAX7- ﬂk2/ﬂt3 ligand HAE-F 01/13/2005 05:11PM Page 104

104 ﬂag

Figure 28 Flow cytometry immunophenotyping. The results of immunophenotyping performed by ﬂow cytometry on the peripheral blood cells of a patient with lymphocytosis. Forward and sideways light scatter have been used to gate on lymphocytes (top left), which have then been further analysed. The lymphocytosis resulted from an increase of CD8-positive lymphocytes (bottom left) with a reversal of the normal CD4:CD8 ratio. However, in addition, there is a population of lambda-positive B cells with a striking reversal of the normal kappa:lambda ratio. The patient had both a post-splenectomy lymphocytosis and circulating follicular lymphoma cells.

flag jargon for an automated instrument that are flowing through a detection device; indication that a blood sample shows an may be based on fluorescence, light scat- abnormality ter, light absorbance or impedance meas- flagging jargon indicating production urements; used for immunophenotyping of ‘flags’ by an automated instrument, (Fig. 28) indicating abnormal or possibly un- flow karyotyping the use of flow cyto- reliable test results metry to identify/separate chromosomes FLI1 a gene, Friend Leukaemia virus on the basis of their DNA content Integration 1, gene map locus 11q24, FLT3 a gene, FMS-Like Tyrosine kinase 3 encodes an ETS transcription factor; receptor, also known as stem cell tyrosine contributes to a EWS-FLI1 fusion gene kinase, gene map locus 13q12, encodes a in Ewing’s sarcoma associated with receptor tyrosine kinase of the PDGFR t(11;22)(q24;q12) superfamily and is the receptor for flt3 flow cytometry the process of evaluat- ligand; expression in human blood and ing characteristics of cells, in suspension, bone marrow cells is restricted to CD34+ HAE-F 01/13/2005 05:11PM Page 105

forkhead domain 105

cells; in frame internal tandem duplica- fibronectin deficiency has been identified tions affecting the JM domain of the flt3 in association with Ehlers-Danlos syn- protein are found in blast cell genomic drome (type X). DNA from approximately 20% of adult foamy macrophage a macrophage patients with acute myeloid leukaemia, with heavily vacuolated cytoplasm, usu- across all FAB subtypes, usually in the ally indicative of the presence of lipid absence of detectable cytogenetic abnor- folate a generic term for folic acid and malities; FLT3 mutations are associated related compounds which are essential with a worse prognosis; mutations are for normal DNA synthesis also present in some patients with folic acid pteroylglutamic acid, one of myelodysplastic syndromes the B group of vitamins, essential for fludarabine a nucleoside analogue used nucleic acid synthesis in treating chronic lymphocytic leukaemia folinic acid N5-formyltetrahydrofolic fluorescence activated cell sorter acid, a form of folate that can circumvent (FACS) an instrument that can sort cells the block in folate metabolism caused by into those that have bound or not bound dihydrofolate reductase inhibitors such a fluorochrome-labelled antibody as methotrexate fluorescence in situ hybridization follicle centre cell a type of mature (FISH) identification of DNA or RNA B lymphocyte found in the follicles of sequences in cells in metaphase or inter- lymph nodes; includes centrocytes (small phase following hybridization with com- cells with condensed chromatin) and plementary RNA or DNA probes that centroblasts (larger cells which may be have been labelled with a fluorochrome nucleolated) fluorescence resonance energy trans- follicle centre cell lymphoma see fer (FRET) the non-radiative transfer follicular lymphoma of energy from a fluorophore in an ex- follicular dendritic cell an antigen- cited state to a nearby acceptor fluoro- presenting cell in lymphoid follicles that phore; the farther apart the two molecules presents antigen to germinal centre B are, the weaker the transfer efficiency; so lymphocytes the technique is useful in assessing the follicular lymphoma a lymphoma interaction between two different (labelled) composed of cells analogous to those macromolecules in the follicles of normal lymph nodes; fluorochrome a fluorescent chemical such lymphomas usually have a follicular FMC7 a monoclonal antibody which structure but sometimes the growth pat- gives positive reactions with cells of most tern is diffuse non-Hodgkin’s lymphomas but not with fondaparinux a synthetic factor Xa the cells of chronic lymphocytic leuk- inhibitor aemia, acute lymphoblastic leukaemia FOP a gene, FGFR1 Oncogene Partner; or lymphoblastic lymphoma, thought to gene map locus 6q27, encodes a ubiquit- recognize a conformational epitope of ously expressed leucine rich repeat (LRR) CD20 protein, that contributes to the FOP- FMS see CSF1R FGFR1 fusion gene in the lympho- FN1 a gene, Fibronectin, also known proliferative–myeloproliferative disorder as Large, External, Transformation- associated with t(6;8)(q27;p11) (see also Sensitive protein, LETS; gene map locus 8p11 syndrome) 2q31, encodes a high molecular weight foreign body giant cell a giant cell of cell surface glycoprotein that also repres- monocyte/macrophage lineage with mul- ents about 1% of serum protein, and is tiple nuclei spread through the cytoplasm required by most cells to bind to collagen; forkhead domain a phosphoprotein FN1 contributed to a NUP98-FN1 fusion binding motif originally identified in a gene, one of two fusion genes present in a group of forkhead transcription factors case of M2 acute myeloid leukaemia; e.g. FKHR, but also present in a wide HAE-F 01/13/2005 05:11PM Page 106

106 formalin

variety of other proteins e.g. the nuclear encodes a glycine-rich protein which is proliferative antigen Ki-67 which is in- a component of nuclear riboprotein volved in centrosome separation during complexes that plays a role in genomic mitosis stability; contributes to the FUS-ERG formalin a solution of formaldehyde, fusion gene in acute myeloid leukaemia used for fixing tissues associated with t(16;21)(p11;q22) FOS a transcription factor of the leucine FUT1 a locus on chromosome 19 with two zipper family alleles relevant to ABH blood group anti- FOS a gene, Finkel-Biskis-Jinkins (FBJ) gens: the H allele encodes α-2-fucosyl- murine Osteosarcoma viral oncogene transferase, which converts the h antigen homologue, gene map locus 14q24.3, to the H antigen; the h allele does not encodes a major component of the encode a transferase (see Fig. 3, p. 4) activator protein-1 (AP-1) transcription FUT2 a locus at 19q13 with two alleles rel- factor complex; expressed at high levels evant to secretor status and Lewis blood in term placenta and trophoblastic cells; group antigens (Fig. 30, p. 108) : the Se transforms cells through alterations in allele encodes α-2-L-fucosyltransferase, DNA methylation and in histone deace- which converts a precursor type 1 disac- tylation; expression in chronic granulocytic charide on a plasma glycosphingolipid leukaemia correlates with interferon- molecule to the H type 1 antigen without alpha responsiveness which the Leb antigen cannot be synthe- fragment (of red cell) a schistocyte or sized; the se allele does not encode a erythrocyte fragment transferase; individuals who are SeSe or frame-shift mutation a deletion or inser- Sese have ABH antigens in saliva and tion of a number of base pairs that is not other body fluids whereas sese individuals either 3 or a multiple of 3, into a DNA do not; the former are referred to as ‘secre- molecule, so that the reading frame is altered tors’ and the latter as ‘non-secretors’; French–American–British (FAB) Co- homozygosity for Se also leads to an operative Group an international increased plasma concentration of von cooperative group of haematologists who Willebrand factor proposed a number of widely accepted FUT3 a locus at 19p13.3 with two alleles classifications of leukaemia and myelody- relevant to Lewis blood group antigens splastic syndromes (see Fig. 30, p. 108): the Le allele encodes fresh frozen plasma (FFP) plasma α-3/4-L-fucosyltransferase, which con- from a single blood donation that has verts a precursor type 1 disaccharide on a been frozen, shortly after separation glycosphingolipid molecule to the Lea from red cells, to a core temperature of antigen, H type 1 antigen to Leb and A below –30°C and which therefore retains type 1 or B type 1 to ALeb or BLeb respec- normal levels of coagulation factors tively; the le allele does not encode a FRET fluorescence resonance energy transfer transferase fusion the process of joining together to FY a locus at 1q21-22 where allelic genes form a fusion gene, composed of parts of encode antigens of the Duffy blood group two genes, or a fusion protein, the prod- system; the genes at this locus are Fya, uct of such a gene (Fig. 29) Fyb, Fyx and Fy; Fyx leads to weak FUS a gene, Fusion, derived from 12-16 expression of the Fyb antigen; Fy has a translocation, malignant liposarcoma; promoter mutation and when this gene gene map locus 16p11.2, also known as is homozygously present the phenotype Translocated in Liposarcoma (TLS); is Fy(a-b-) HAE-F 01/13/2005 05:11PM Page 107

FY 107

Figure 29 Fusion genes and fusion proteins. Two fusion genes involving CBFA2 and CBFB, encoding CBFα2 and CBFβ respectively illustrate the role of fusion genes and chimaeric proteins in oncogenesis. (a) CBFα2 and CBFβ together form a heterodimeric haemopoietic transcription factor, Core Binding Factor (CBF). CBFβ does not itself bind to DNA but interacts via its CBFα binding domain (CBFα BD) with CBFα2. This interaction occurs in the runt domain of CBFα2 and increases the ability of another part of the runt domain to bind the consensus DNA sequence YGYGGT. Once bound to DNA, CBF can activate transcription of a large number of haemopoietic genes. In certain circumstances it can act as a repressor via the VWRPY motif at the carboxy terminus of CBFα2 which interacts with the transcriptional repressor, TLE. Normally, CBFα2 is sequestered in the nucleus due to its nuclear matrix-binding domain NMTS. (b) The acquired chromosomal abnormality inv(16)(p13q32) seen in a speciﬁc subtype of AML, leads to the fusion of most of the CBFB gene to the region encoding the tail domain of the smooth muscle myosin heavy chain (SMMHC or MYH11) gene. Several variants of a CBFB-SMMHC fusion transcript have been detected in AMLs with inv(16). Most lead to a fusion protein containing a fully functional CBFα BD fused to the α-helical tail of SMMHC. The fusion protein is able to form multimers because of this tail, which can be visualized as nuclear and cytoplasmic speckles. It is believed that multimeric CBFβ-SMMHC sequesters CBFα2 subunits and so reduces DNA binding by CBF. (c) The translocation t(8;21)(q22;q22) seen in another subtype of AML, leads to the fusion of the runt domain of the CBFA2 gene to the majority of ETO which encodes a non-DNA binding nuclear protein involved in the recruitment of histone deacetylses. The ETO protein has ‘nervy’ domains that permit interactions with transcriptional repressors. The CBFα2-ETO fusion protein is able to interact with CBFβ and does so with greater afﬁnity than wild-type CBFα2, but the ETO moiety leads to the repression of transcription. This leads to a differentiation arrest in myeloid cells.

(a) Wild type CBF CBFβ α VWRPY CBF BD CBFα CBFβ + Runt NMTS VWRPY Transcription CBFα2 YGYGGT

CBFα sequestered from DNA (b) inv(16) CBFα BD Myosin heavy chain CBFβ-SMMHC inv(16)

Myosin heavy chain YGYGGT – Transcription

Repressor proteins (c) t(8;21) ETO NN Histone CBFα–ETO t(8;21) acetylation

YGYGGT – Transcription HAE-F 01/13/2005 05:11PM Page 108

108 FY

Figure 30 The Lewis blood group system. The interaction between transferases encoded by three sets of allelic genes to produce Lewis blood group antigens: (a) In an individual who is A positive (genotype either AA or AO), Le positive (genotype LeLe or Lele) and who is a ‘secretor’ (genotype SeSe or Sese). The Le allele at the FUT3 locus encodes a transferase that converts a precursor to Lea antigen whereas the Se allele at the FUT1 locus produces H type 1 which can be converted by the transferase encoded by Le into Leb. In the presence of the transferase encoded by the A allele at the ABO locus A Leb is also produced. The phenotype is A Le(a+b+). (b) In an individual who is A positive (genotype either AA or AO) and Le positive (genotype LeLe or Lele) but who is a ‘non-secretor’ (genotype sese) Lea is the only Lewis antigen produced. The phenotype is A Le(a+b–).

Genotype (a) AA SeSe LeLe Type 1disaccharide (mainly in plasma)

α-2-L-fucosyltransferase α-3/4-L-fucosyltransferase (encoded by Se (encoded by Le at FUT2 locus) at FUT3 locus)

a H type 1 Le

α-3-N-acetyl-D- galactosaminyltransferase α-3/4-L-fucosyltransferase (encoded by A at ABO locus)

A type 1 Leb

α-3/4-L-fucosyltransferase

Leb

Final phenotype: A Le(a+b+) 'secretor'

(b) Type 1 disaccharide Genotype AA SeSe LeLe

α-3/4-L-fucosyltransferase

Lea

Final phenotype: A Le(a+b–) 'non-secretor' HAE-G 01/13/2005 05:11PM Page 109

γ the Greek letter gamma driving cells into G0 phase; deleted in γ chain (i) the γ globin chain which forms many myeloid neoplasms part of haemoglobin F (ii) the heavy GAS2 a gene, Growth Arrest-Specific 2; chain of an immunoglobulin G molecule; gene map locus 11p15.2-p14.3; encodes a two γ chains combine with two light ubiquitously expressed component of the chains, in an individual molecule either microfilament system which increases κ or λ, to form an immunoglobulin susceptibility to p53-dependent apoptosis molecule (iii) part of the γδ T-cell recep- GAS6 a gene, Growth Arrest-Specific 6, tor, a surface membrane structure which also known as Axl receptor tyrosine permits antigen recognition kinase Ligand, AXLLG; gene map locus γ-glutamyl cysteine synthetase (an 13q34; encodes a vitamin K-dependent enzyme of the pentose shunt) protein homologous to protein S which is hexose monophosphate shunt the ligand for the receptor tyrosine kinase (see Fig. 59, p. 182) AXL γ heavy chain disease a plasma cell GAS7 a gene, Growth Arrest-Specific 7; dyscrasia in which there is secretion of gene map locus 17p13, encodes a putative monoclonal γ chain transcription factor expressed normally G an abbreviation for the purine, guanine in the brain, that contributed to a MLL- G0, G1 and G2 three phases of the cell GAS7 fusion gene in a case of therapy- cycle (see Fig. 15, p. 72) related M4 acute myeloid leukaemia with G6PD glucose-6-phosphate dehydrogenase a cryptic t(11;17)(q23;p13) translocation G6PD the gene at Xq28 encoding glucose- GAS41 a gene, Glioma-Associated Seq- 6-phosphate dehydrogenase; mutation uence 41, gene map locus 12q13-q15, may lead to glucose-6-phosphate dehydro- encodes a putative transcription factor genase deficiency with intermittent or, that has homology with AF9 and ENL; much less often, chronic, haemolysis GAS41 amplified in high-grade glioma gallium scan an imaging technique GATA-1 a gene encoding a transcrip- using 67Ga-single photon emission com- tion factor that is important in erythro- puterized tomography to detect meta- poiesis and critical in megakaryocyte bolic activity in residual areas of active differentiation lymphoma Gaucher cell the characteristic altered gamete a germ cell, a spermatozoon or macrophage of Gaucher’s disease an ovum Gaucher’s disease hereditary glucosyl GAP GTP-ase activating protein ceramide lipidosis, a heterogeneous group GAS1 a gene, Growth Arrest-Specific 1; of inherited diseases resulting from var- gene map locus 9q21.3-q22.1; encodes a ious mutations in the glucocerebrosidase plasma membrane protein which is a gene; these mutations lead to accumula- homologue of the iron protein subunit of tion of glucocerebroside in character- Complex I of the mitochondrial electron istic macrophages, designated Gaucher transport chain; expressed in non- cells; may be diagnosed by bone marrow transformed cells in response to stimuli aspiration

109 HAE-G 01/13/2005 05:11PM Page 110

110 Gaussian

Figure 31 G banding. A karyogram of G-banded chromosomes of a patient with chronic granulocytic leukaemia. The banding pattern produced by the Giemsa stain, together with a consideration of the size of the chromosome and the position of the centromere, permits the identiﬁcation of individual chromosomes, normal and abnormal. There is a t(9;22)(q34;q11); this is a balanced translocation between chromosomes 9 and 22 with breakpoints at 9q34 and 22q11 respectively.

Gaussian a description of data that, GDP guanosine diphosphate when plotted as a histogram, have a bell- GEF guanine nucleotide exchange factor shaped distribution; also referred to as a gelatinous transformation deposi- ‘normal distribution’ (see Fig. 45, p. 128) tion of acid mucopolysaccharide in bone GBA the gene encoding glucocerebrosi- marrow, replacing haemopoietic tissue dase, mutated in Gaucher’s disease gene the segment of DNA that is in- G-banding a technique for staining meta- volved in producing a polypeptide chain; phase spreads of chromosomes with a it includes regions preceding and follow- Giemsa stain to produce a unique banding the coding region (5′ and 3′ untrans- ing pattern that permits the identiﬁcation lated regions) as well as intervening of individual chromosomes (Fig. 31) sequences (introns) between individual G-CFU granulocyte colony-forming unit coding segments (exons) (Fig. 32); genes G-CSF granulocyte colony-stimulating mediate inheritance; they are located on factor nuclear chromosome or, rarely, on a GCSFR a gene, Granulocyte Colony- mitochondrion Stimulating Factor Receptor, also known gene expression the transcription of a as Colony-Stimulating Factor 3 Recep- gene into tRNA, rRNA or mRNA, in the tor, CSF3R, CD114; gene map locus latter case with subsequent translation to 1p35-p34.3; encodes the G-CSF receptor; protein point mutations in this gene have been gene proﬁling see microarray analysis reported in some patients with severe genetic pertaining to inheritance by genes congenital neutropenia (Kostmann’s genetic code the relationship between a syndrome), these patients being at great- triplet of bases, called a codon, and the est risk of developing myelodysplastic amino acid which it encodes syndrome or acute myeloid leukaemia; genome the complete DNA sequence of mutation leading to synthesis of a trun- an individual or a species cated protein has also been implicated in genomic pertaining to a gene or genes acute myeloid leukaemia complicating genotype the genetic makeup of an indi- Kostmann’s syndrome vidual, cf. phenotype HAE-G 01/13/2005 05:11PM Page 111

Gilbert’s syndrome 111

Figure 32 Gene structure and function. A gene is a segment of DNA that is involved in producing a protein. It is also known as a transcriptional unit and includes not only coding regions (exons), but also non-coding sequences which lie between exons (introns), and before and after the coding segments (5′ and 3′ untranslated regions). Transcription is the enzymatic process whereby RNA is synthesized from a DNA template. The promoter is the section of DNA where the transcriptional machinery binds before transcription can start. It is defined by certain highly conserved sequences, e.g. the TATA box which is found 25bp ‘upstream’ from (i.e. 5′ to) the transcriptional start site, and the CAAT box, found 75bp upstream. Transcriptional termination signals lie in the 3′UTR and trigger the 3′ cleavage of newly formed RNA (see Figure 65, p. 202). The first coding triplet in a gene is referred to as the start codon and is usually ATG (encoding methionine); the coding sequence always ends in a termination signal (a codon which does not encode an amino acid); this can be TAG, TGA or TAA. Translation is the synthesis of a protein from a messenger RNA (mRNA) template; this always proceeds from a start codon to a stop codon. Some genes have multiple promoters and may have introns spanning several Kb. There are many examples of overlapping genes and of transcription in either orientation occurring from different promoters in the same segment of DNA. The flanking sequences on either side or within the transcriptional unit may contain enhancers, which are sequences of DNA involved in the binding of positive or negative transcriptional regulatory proteins.

Start Stop codon codon ATG e.g. TAG Promotor 3'UTR

Flanking region 5'UTR Flanking region enhancer enhancers Transcriptional unit

Exon Untranslated region, UTR

Intron Direction of transcription

Gerbich antigen an erythrocyte mem- giant metamyelocyte a metamyelo- brane antigen, carried on glycophorin C; cyte which is two to three times normal monoclonal antibodies to this antigen size and often has a nucleus of abnormal can be used for the identification of ery- shape, characteristic of megaloblastic throid cells erythropoiesis germ cell a gamete, a spermatozoon or Giemsa stain a Romanowsky type an ovum stain which can be used for staining blood germinal centre a specialized structure and bone marrow cells and tissue sections in a lymph node or other lymphoid tissue and is also used for staining preparations in which follicular dendritic cells present of chromosomes (see G-banding); one antigen to B lymphocytes component of a May–Grünwald–Giemsa ghost cell an erythrocyte which contains stain negligible amounts of haemoglobin GIFT granulocyte immunofluorescence test giant cell arteritis inflammation of Gilbert’s syndrome a common syn- arteries with the inflammatory cells in- drome resulting from homozygosity for cluding giant cells, usually associated a polymorphism in the promoter region with a high erythrocyte sedimentation of the gene encoding bilirubin UDP glu- rate, which can therefore be used as a curonosyl transferase-1, UGT1, leading diagnostic aid to unconjugated hyperbilirubinaemia; it HAE-G 01/13/2005 05:11PM Page 112

112 gingivitis

causes neonatal jaundice in infants with pathway in erythrocytes and other cells in G6PD deficiency and aggravates jaundice which glucose is broken down to provide in adults with haemolytic anaemias energy for the cell (Fig. 33) gingivitis inflammation of the gums, glycophorin a group of red cell mem- can be a feature of acute leukaemia brane proteins, glycophorins A, B, C and with monocytic differentiation D (CD235a, CD235b, CD236, CD236R), gland (i) specialized epithelial tissue antibodies to which can be used to iden- capable of secretion (ii) a popular term tify cells of erythroid lineage (see Fig. 64, for a lymph node p. 199, and see also GYPA, GYPB, GYPC) glandular fever see infectious mononu- glycoprotein a post-translationally cleosis modified protein in which a carbohydr- Glanzmann’s thrombasthenia a severe, ate is covalently linked to an amino acid autosomal recessive, inherited defect of residue platelet function, resulting from muta- glycosaminoglycan a polysaccharide tion in either the ITGA2B or the ITGB3 consisting of repeating disaccharide gene, leading to deficiency of platelet gly- units of amino sugar derivatives (such as coprotein IIb/IIIa glucosamine or galactosamine), at least globin the protein part of the haemo- one of which has a negatively charged globin molecule carboxylate or sulphate group; heparin globoside collection blood group anti- and heparan are glycosaminoglycans gens, P and Pk, closely related to the P glycoside a substance with an alcohol blood group system component in which a glycosyl (sugar) glomerulonephritis inflammation of moiety has replaced the hydrogen in the glomeruli hydroxyl group glomerulus (plural glomeruli) the glycosylation the process in which a structure in the kidney in which filtration covalent bond is formed between glucose occurs, leading to formation of urine and a macromolecule glossitis inflammation of the tongue, a glycosylphosphatidylinositol (GPI) a

feature of deficiency of iron or vitamin B12 red cell membrane protein, encoded by glucose-6-phosphate dehydrogenase the PIGA gene, that anchors many other (G6PD) an enzyme of the pentose shunt red cell surface membrane proteins, which protects red cells from oxidant including CD55, CD58 and CD59 damage (see Fig. 59, p. 182) GM-CFU granulocyte/macrophage colony- glucose-6-phosphate dehydrogenase forming unit (G6PD) deficiency reduced glucose- GM-CSF granulocyte/macrophage colony- 6-phosphate dehydrogenase activity in stimulating factor red cells leading to susceptibility to GMPS a gene, Guanosine-5′-Mono- oxidant-induced haemolysis phosphate Synthetase, gene map locus glucose phosphate isomerase an 3q24, encodes the enzyme that catalyses enzyme in the erythrocyte glycolytic the amination of xanthylate (XMP) to pathway (Fig. 33) guanylate (GMP) in the purine synthe- glutathione synthetase an enzyme sis pathway; contributed to an MLL- related to the pentose shunt (see Fig. 59, GMPS fusion gene in a patient with p. 182) M4 acute myeloid leukaemia associated glycogen a complex carbohydrate with t(3;11)(q25;q23); in the resulting glycolipid a sugar-containing lipid in chimaeric proteins the catalytic domain which a monosaccharide is linked to a of GMPS was intact lipid via glycosidic bond GMS stain Grocott’s methenamine silver glycolysis the process by which glucose stain is metabolized, providing energy for a cell Golgi apparatus or Golgi complex glycolytic pathway (Embden– stacks of flattened membranous sacs Meyerhof pathway) the metabolic receiving newly synthesized proteins from HAE-G 01/13/2005 05:11PM Page 113

Good Clinical Practice 113

Figure 33 The glycolytic pathway. The glycolytic pathway provides energy for body cells including erythrocytes. Enzymes are shown in italics and enzyme products in upright script. Pyruvate kinase deﬁciency is the most common inherited defect of the glycolytic pathway.

Glucose ATP Hexokinase ADP

Glucose-6-phosphate

Glucosephosphate isomerase

Fructose-6-phosphate

ATP Phosphofructokinase ADP

Fructose-1,6-diphosphate Aldolase

Dihydroxyacetone phosphate Aldolase

Trio sephos isom phate Glyceraldehyde- erase 3-phosphate

Haemoglobin ATP Glyceraldehydephosphate Methaemoglobin ADP dehydrogenase biphosphoglycerate mutase/ Cyochrome b5 reductase biphosphoglycerate kinase 1,3-biphosphoglycerate

ADP Phosphoglycerate kinase 2,3-biphosphoglycerate ATP

3-phosphoglycerate biphosphoglycerate mutase/ biphosphoglycerate kinase Phosphoglycerate mutase (and diphosphoglycerate mutatase)

2-phosphoglycerate

Enolase

Phosphoenolpyruvate

ADP Pyruvate kinase ATP

Pyruvate

NADH Lactate dehydrogenase NAD

Lactate

the endoplasmic reticulum, responsible for complex is located; in cells with a well modiﬁcation, packaging and distribution developed Golgi apparatus the Golgi of proteins zone appears as a pale area Golgi zone the area of a cell, usually Good Clinical Practice a standard for adjacent to the nucleus, where the Golgi the design, conduct, performance, monit- HAE-G 01/13/2005 05:11PM Page 114

114 gout

oring, auditing, recording and reporting dysplastic syndrome associated with of clinical trials that provides assurance t(3;3)(q21;q26) and inv(3)(q21q26) that the data and reported results are grade an expression of the degree of credible and accurate and that the rights, malignancy of a tumour integrity and confidentiality of trial sub- GRAF a gene, RhoA GTPase Regulation jects are protected Associated with Focal adhesion kinase gout acute crystal arthropathy second- pp125, gene map locus 5q31, encodes an ary to urate deposition; may be a feature SH3 domain-containing protein which is of myeloproliferative disorders, causes highly homologous to BCR; a member neutrophilia of the GTPase-activating protein (GAP) GP1BA a gene, gene map locus 17pter- family; binds to pp125(FAK), a tyrosine p12, encoding platelet glycoprotein Ibα, kinase involved in the integrin signalling mutation of which can lead to Bernard– transduction pathway, also stimulates Soulier syndrome and platelet-type von the GTPase activity of RhoA; GRAF con- Willebrand’s disease tributed to a MLL-GRAF fusion gene in GP1BB a gene, gene map locus 22q11.2, a child with juvenile myelomonocytic encoding platelet glycoprotein Ibβ, muta- leukaemia associated with t(5;11)(q31;q23); tion of which can lead to Bernard–Soulier both alleles of the gene were also dis- syndrome rupted in three cases of acute myeloid GPV a gene on chromosome 3 encoding leukaemia–myelodysplastic syndrome platelet glycoprotein V, mutation of which associated with 5q– can lead to Bernard–Soulier syndrome graft a tissue that is transplanted into GPIX a gene on chromosome 3 encoding another individual or, less accurately, platelet glycoprotein IX, mutation of which that is removed from an individual and can lead to Bernard–Soulier syndrome subsequently returned GPH a gene, Gephyrin, gene map locus graft rejection the process by which a 14q24, encodes gephyrin—a protein transplanted tissue, e.g. bone marrow, is expressed in the brain which is involved recognized as foreign and rejected by the in anchoring the inhibitory glycine recep- body tor to the postsynaptic cytoskeleton; graft-versus-host disease (GVHD) several alternative transcripts are known the illness resulting from engraftment of which differ at their 5′ termini, but immunocompetent lymphoid cells that which encode the same 3′ tubulin bind- recognize host tissues as foreign and ing site; also known as GPNH; con- attack them tributed to a MLL-GPNH fusion gene in graft-versus-leukaemia (GVL) the abil- t(11;14)(q23;q24) in a patient with M5b ity of engrafted tissue to exert a specific acute myeloid leukaemia and in a patient anti-leukaemic effect that is different from with ‘undifferentiated’ acute leukaemia the generalized graft-versus-host effect following therapy with a topoisomerase Gram-negative non-staining with a II-interactive drug in which the fusion Gram stain protein retained the gephyrin tubulin Gram-positive staining with a Gram stain binding site; autoantibodies to gephyrin Gram stain a stain used for staining have been observed in a patient with stiff bacteria, which are then classified as man syndrome Gram-positive or Gram-negative GR6 a gene located within the leukaemia granulocyte a leucocyte with a lobed breakpoint region of 3q21, gene map nucleus and granular cytoplasm—a locus 3q21, expressed in early fetal devel- neutrophil, eosinophil or basophil opment but not in adult peripheral blood granulocyte-colony forming unit cells; has no known homologies; GR6 (G-CFU) a progenitor cell that can give contributes to an GR6-EVI1 fusion gene rise to a colony of granulocytes when in acute myeloid leukaemia and myelo- cultured in vitro HAE-G 01/13/2005 05:11PM Page 115

GYPC 115

granulocyte-colony stimulating fac- Griscelli syndrome partial albinism tor (G-CSF) a cytokine that promotes with immunodeficiency—defective nat- granulopoiesis, leading to an increased ural killer cell function, absent delayed neutrophil count in vivo and supporting hypersensitivity reactions and sometimes growth of granulocyte colonies in vitro, secondary hypogammaglobulinaemia encoded by a gene at 17q11.2-21; recom- Grocott’s methenamine silver (GMS) binant G-CSF is available as a therapeu- stain a stain used for the detection of tic product fungi granulocyte immunofluorescence growth factor a protein secreted by one test (GIFT) a test for anti-neutrophil cell that promotes growth of cells of antibodies another lineage granulocyte/macrophage colony- GSH2 a gene, gene map locus 4q11, forming unit (GM-CFU) a progenitor encoding a brain-specific homeobox cell which can give rise to a mixed colony gene homologous to the Drosophila of granulocytes and macrophages on in gene ‘intermediate neuroblasts defective’ vitro culture (ind); GSH2 is upstream of the CHIC2- granulocyte/macrophage colony- ETV6/TEL fusion gene and is dysregu- stimulating factor (GM-CSF) a lated in acute myeloid leukaemia haemopoietic growth factor, synthesized associated with t(4;12)(q11;p13) by B cells, T cells, NK cells and macro- GTP guanosine triphosphate phages, which stimulates production of guanine a purine base of DNA or RNA, granulocytes and macrophages, leading pairs with cytosine to neutrophilia and monocytosis in vivo guanine nucleotide exchange factors and sustaining growth of, mixed granulo- (GEFs) a family of molecules that bind cyte/macrophage colonies in vitro, to inactive GTPases, e.g. Rho, RAS and encoded by a gene at 5q31 RAC, and induce conformational changes granulocytic sarcoma chloroma, a soft allowing GDP release and replacement tissue tumour composed of leukaemic by GTP (see also RAS) myeloblasts with or without maturing GVHD graft-versus-host disease cells GVL graft-versus-leukaemia granuloma (i) a cohesive cluster of GYPA a gene at 4q28.2-q31.1, also known epithelioid macrophages with or without as GPA and MN locus, encoding gly- lymphocytes and other inflammatory cells cophorin A; the M and N antigens are (ii) a cohesive cluster of altered macro- encoded by alleles of GYPA phages containing lipid vacuoles GYPB a gene at 4q28.2-q31.1, also known granulomere the granular part of a as GPB and Ss locus, encoding glyco- platelet phorin B; the S and s antigens are encoded granulopoiesis the process by which by alleles of GYPB granulocytes are produced (see Fig. 25, GYPC a gene at 2q14-q24 encoding p. 95) glycophorin C and glycophorin D, which grey platelet syndrome an inherited carries the Gerbich blood group antigens platelet defect in which platelets lack α granules and thus, when stained, appear pale blue or grey and agranular HAE-H 01/13/2005 05:12PM Page 116

H4(10S170) a gene, gene map locus Figure 34 Haem synthesis. 10q21, encoding a leucine zipper protein The process by which haem is synthesized. Enzymes the function of which is unknown; con- are shown in italics and enzyme products in upright tributes to: script. • a fusion gene, H4(10S17)-PDGFRB, Glycine + succinyl Coa in atypical chronic myeloid leukaemia associated with t(5;10)(q33;q22); ala-synthase + pyridoxal-5'- • an H4-BCL6 fusion gene in non- phosphate Hodgkin’s lymphoma; δ The leucine zipper domain is present Mitochondrion aminolaevulinic acid in the chimaeric proteins generated in each of these cases and permits their ala-dehydrase oligomerization H & E haematoxylin and eosin stain Porphobilinogen HAART highly active antiretroviral therapy Porphobilinogen deaminase haem a porphyrin structure that contains iron and that forms part of the Hydroxymethylbilane haemoglobin molecule; it is synthesized partly within mitochondria and partly in Cytosol Uroporphyrinogen the cytosol (Fig. 34) III synthase haematemesis the vomiting of blood Uroporphyrinogen III haematocrit (Hct) the proportion of a column of centrifuged blood which is Uroporphyrinogen occupied by erythrocytes or an equiva- III decarboxylase lent estimation produced by an automated blood counter Coproporphyrinogen III haematogone a primitive lymphoid cell Coproporphyrinogen which morphologically resembles a lym- III oxidase phoblast but is a normal reactive cell haematology the study of blood and its Protoporphyrinogen III diseases Protoporphyrinogen haematopoiesis a synonym for haem- III oxidase opoiesis, this term being generally used in

the USA Mitochondrion Protoporphyrin IX haematopoietic pertaining to haematopoiesis, a synonym for haemopoietic, Ferrochelatase this term being generally used in the USA Fe2+ haematoxylin a basic dye used in cytology Haem and to stain parasites; used in combination with eosin to stain tissue sections

116 HAE-H 01/13/2005 05:12PM Page 117

haemoglobin electrophoresis 117

haematoxylin and eosin (H & E) the Figure 35 The haemoglobin molecule. standard stain used for staining tissue A sketch of the haemoglobin molecule showing that α β sections, a mixture of basic haemotoxylin it is composed of two globin chains and two and acidic eosin globin chains, each enclosing a haem moiety. haematuria the presence of red cells in the urine β β 2 1 haemiglobin cyanide an alternative designation of cyanmethaemoglobin, the form of haemoglobin which results from interaction with cyanide in the cyanmethaemoglobin method for estimation of haemoglobin concentration haemochromatosis see hereditary haemochromatosis α α haemocytometer a counting chamber 2 1 for counting blood cells haemodialysis a method of treating acute or chronic renal failure by passing the patient’s blood through a dialysis machine; blood and dialysis fluid are separated by a semipermeable membrane so haemoglobin C a variant haemoglobin that exchange of solutes can occur with an amino acid substitution in the haemoflagellates flagellated blood par- beta chain, mainly found in those of asites such as trypanosomes and leishmania African ancestry haemoglobin a complex molecule com- haemoglobin Constant Spring a posed of four globin chains, each of which variant haemoglobin with a structurally partially encloses a haem molecule abnormal alpha chain which is synthe- (Fig. 35), which has as its major function sized at a reduced rate, leading to α the transport of oxygen from the lungs to thalassaemia the tissues haemoglobin D the designation of a haemoglobin A the major haemoglobin group of haemoglobin variants, some α component present in most adults, hav- chain variants and some β chain variants, ing two α chains and two β chains that have the same mobility as haemo- haemoglobin A2 a minor haemoglobin globin S on haemoglobin electrophoresis component present in adults and, as an at alkaline pH even lower proportion of total haemo- haemoglobin dissociation curve a globin, in neonates and infants; it has two plot of percentage saturation of haemo- α chains and two δ chains globin against partial pressure of oxygen haemoglobin Bart’s an abnormal (Fig. 37) haemoglobin with four γ chains and no Haemoglobin Distribution Width α chains, present as the major haemo- (HDW) a measurement made by some globin component in haemoglobin Bart’s automated blood counters that indicates hydrops fetalis and as a minor component the amount of variation in haemoglobin in neonates with haemoglobin H disease concentration between erythrocytes; an or alpha thalassaemia trait increased HDW correlates with aniso- haemoglobin Bart’s hydrops fetalis chromasia on a blood film a fatal condition of a fetus or neonate, haemoglobin E a variant haemoglobin resulting from homozygosity or compound with an amino acid substitution in the heterozygosity for α0 thalassaemia beta chain, mainly found in South-east (Fig. 36); as there are no alpha genes Asia and parts of the Indian subcontinent there can be no production of haemo- haemoglobin electrophoresis a me-

globin A, A2 or F thod of separating normal and variant HAE-H 01/13/2005 05:12PM Page 118

118 haemoglobin F

Figure 36 haemoglobin Bart’s hydrops fetalis. A diagrammatic representation of the possible outcomes in a family at risk of producing a fetus with haemoglobin Bart’s hydrops fetalis.

Mother Father α0 thalassaemia α0 thalassaemia heterozygosity heterozygosity

Hb Bart's α thalassaemia α thalassaemia Normal hydrops fetalis trait trait (homozygosity (heterozygosity (heterozygosity for α0 for α0 for α0 thalassaemia) thalassaemia) thalassaemia)

haemoglobins from each by applying a haemolysate to a membrane or gel across Figure 37 A haemoglobin dissociation curve. which there is an electrical gradient; the A haemoglobin dissociation curve showing the sigmoid form of the normal dissociation curve and pH and the nature of the membrane or gel the factors which shift the curve to the left or right. determines the rate at which different haemoglobins migrate in the electrical 100 Alkalosis ﬁeld (Fig. 38) 90 decreased haemoglobin F fetal haemoglobin, the 2,3BPG 80 major haemoglobin of the fetus and neonate (Fig. 39), which is present as a 70 very minor component in most adults 60 Acidosis and in higher amounts in a minority; 50 increased adult levels have usually been reached by 40 2,3BPG about one year of age fever haemoglobin G the designation of a 30 group of haemoglobin variants, some of 20 which are alpha chain variants and some 10 of which are beta chain variants, that 0 have the same mobility as haemoglobin S 2.5 5 7.5 10 12.5 on haemoglobin electrophoresis at alka- kPa line pH; whether a variant haemoglobin HAE-H 01/13/2005 05:12PM Page 119

haemoglobin Lepore 119

Figure 38 Haemoglobin electrophoresis. is designated haemoglobin D or haemo- The results of haemoglobin electrophoresis on a globin G is completely arbitrary cellulose acetate membrane at alkaline pH. haemoglobin Gower an embryonic Haemoglobins S, D and G move together, as do haemoglobin; haemoglobin Gower 1 is haemoglobins C, E and A : (a) haemoglobins S and 2 ζ ε α ε C; (b) haemoglobin S; (c) haemoglobins A and C; 2 2 and haemoglobin Gower 2 is 2 2 (d) haemoglobin S; (e) haemoglobins A and C; haemoglobin H a variant haemoglobin (f) haemoglobins S and C; (g) haemoglobins A and with four β chains and no α chains, C; (AFSC) control sample containing haemoglobins present in haemoglobin H disease and, in A, F, S and C. small quantities, in α thalassaemia trait haemoglobin H disease a thalassaemic condition caused by marked underproduction of α chains, often but not always resulting from compound heterozygosity for α+ thalassaemia and α0 thalassaemia with consequent lack of three of the four alpha genes (Fig. 40) haemoglobin H inclusions small round evenly dispersed erythrocyte inclusions composed of haemoglobin H; they can be stained with vital dyes haemoglobin Lepore a variant haemoglobin resulting from the fusion of part of a δ globin gene with part of

Figure 39 Changes if haemoglobin F percentage during development. The proportions of haemoglobin F and other normal haemoglobins present in the embryo, fetus, neonate and infant.

100 90 80 Haemoglobin F 70 60 50

40 Haemoglobin A 30

Total haemoglobin (%) Total 20 10 Haemoglobin A2 0 5 16 28 0 3 6 9 Weeks from conception Months of age

Haemoglobins Gower 1, Gower 2, and Portland Birth HAE-H 01/13/2005 05:12PM Page 120

120 haemoglobinopathy

Figure 40 Haemoglobin H disease. A diagrammatic representation of the possible outcomes in a family at risk of producing a child with haemoglobin H disease.

Mother Father α+ thalassaemia α0 thalassaemia heterozygosity heterozygosity

Hb H disease α thalassaemia α thalassaemia Normal (compound trait trait heterozygosity (heterozygosity (heterozygosity for a+ and α0 for α+ for α0 thalassaemia) thalassaemia) thalassaemia) Children

a β globin gene, giving a δβ fusion haemoglobinuria the presence of haemo- gene and fusion protein; it is synthes- globin in the urine ized at a slower rate than the β chain haemolysate a solution of haemoglobin and thus is functionally equivalent to a obtained by lysing red cells β thalassaemia haemolysis an increased rate of destruc- haemoglobinopathy an inherited dis- tion of erythrocytes order resulting from synthesis of a haemolytic anaemia anaemia result- structurally abnormal haemoglobin; the ing from an increased rate of destruction term can also be used to encompass, in of erythrocytes addition, the thalassaemias in which haemolytic disease of the newborn there is a reduced rate of synthesis of one (HDN) haemolytic anaemia in a neonate, of the globin chains consequent on destruction of fetal and haemoglobin Portland an embryonic neonatal erythrocytes by a maternal allo- ζ γ haemoglobin, 2 2 antibody which has crossed the placenta haemoglobin S sickle cell haemoglobin, haemolytic uraemic syndrome (HUS) a variant haemoglobin with a tendency a syndrome of microangiopathic haemo- to polymerize at low oxygen tension, lytic anaemia and acute renal failure causing erythrocytes to deform into the haemophagocytic syndrome an ill- shape of a sickle ness resulting from haemophagocytosis, HAE-H 01/13/2005 05:12PM Page 121

heavy chain 121

characterized by pancytopenia and some- hairy cell an abnormal B-lymphocyte times hepatomegaly, splenomegaly and present in hairy cell leukaemia, analogous fever, see also familial haemophagocytic to a late B cell lymphohistiocytosis hairy cell leukaemia a chronic B- haemophagocytosis phagocytosis of lineage leukaemia with neoplastic cells haemopoietic cells and their progeny which are morphologically and immuno- haemophilia an inherited haemorrhagic phenotypically distinctive disorder resulting from deficiency of fac- hairy cell leukaemia variant a chronic tor VIII (haemophilia A, resulting from a B-lineage leukaemia with neoplastic cells mutation in the F8C gene) or factor IX which resemble the cells of hairy cell leuk- (haemophilia B, resulting from a muta- aemia morphologically but with there tion in the F9 gene) being differences in immunophenotype haemophilia A an X-linked recessive and haematological and clinical features inherited bleeding disorder (see Fig. 68, Ham test see acid lysis test p. 207) resulting from a mutation, most HAM HTLV-I-associated myelopathy often an inversion that splits the gene, hand mirror cell a blast cell shaped like involving the F8C gene a mirror, may be of lymphoid or myeloid haemophilia B an X-linked recessive lineage inherited bleeding disorder, previously Hand–Schüller–Christian disease part known as Christmas disease, resulting of the clinical spectrum of Langerhans from a mutation, most often a point cell histiocytosis mutation, in the F9 gene haploid a description of cells with a com- haemophilia B Leiden a variant of plement of 23 chromosomes, one copy of haemophilia B, resulting from one of a each autosome and either an X or a Y number of point mutations in the pro- chromosome; normal sperm and ova are moter region of the F9 gene, in which haploid but in somatic cells haploidy is factor IX concentration rises at puberty highly abnormal with improvement of the bleeding tend- haploidy the state of having a haploid ency; the likely explanation is that the complement of chromosomes mutations affect a binding region for haplo-insufficiency an abnormal phe- androgen-sensitive transcription factors notype or predisposition to disease as a haemopoiesis the process of produc- result of loss of one allele of a gene or loss tion of blood cells (Fig. 41) of a longer DNA sequence from one of a haemopoietic pertaining to haemopoiesis pair of chromosomes haemopoietic cell a precursor cell giv- haplotype genotype of a group of alleles ing rise ultimately to granulocytes, mono- from two or more closely linked loci, e.g. cytes, erythrocytes and platelets the βS gene occurs in association with haemopoietic growth factor a protein, several different haplotypes often a glycoprotein, that promotes growth hapten a small antigen that becomes and differentiation of haemopoietic cells, immunogenic when complexed with a e.g. erythropoietin, thrombopoietin larger protein haemorrhage bleeding; may be a nor- HC2 a monoclonal antibody which gives mal phenomenon, e.g. following injury, positive reactions with hairy cells and or the result of an inherited or acquired occasionally with cells of other chronic haemorrhagic disorder lymphoproliferative disorders haemorrhagic disease of the new- hCDCre see CDCREL born a haemorrhagic disorder of neo- Hct haematocrit nates consequent on vitamin K deficiency HDN haemolytic disease of the newborn haemosiderin the major storage form HDW Haemoglobin Distribution Width of iron, present in macrophages heavy chain the longer of the two poly- haemostasis the process by which haemo- peptide chains of a dimer, usually refers rrhage is arrested to the heavy chain of an immunoglobulin HAE-H 01/13/2005 05:12PM Page 122

Figure 41 Haemopoiesis. A diagrammatic representation of haemopoiesis showing the stem cell/progenitor cell hierarchy and the growth factors that are thought to act at each stage of development. Abbreviations for cell names: PSC, pluripotent stem cell (also known as HSC, haemopoietic stem cell); CLP, common lymphoid progenitor; T, T cell; B, B cell; NK, natural killer cell; LDC, lymphoid dendritic cell; CMP, common myeloid progenitor (also known as multipotent myeloid stem cell); CFU-GM, colony-forming unit–granulocyte-macrophage; CFU-G, colony-forming unit–granulocyte; CFU-M, colony-forming unit–macrophage; MDC, myeloid dendritic cell; CFU-Eo, colony-forming unit–eosinophil; CFU-Baso, colony- forming unit–basophil; CFU-Mast, colony-forming unit–mast cell; BFU-E, burst-forming unit–erythroid; CFU-E, colony-forming unit–erythroid; BFU-Mega, burst-forming unit–megakaryocyte; CFU-Mega, colony- forming unit–megakaryocyte; HSC, haematopoietic stem cell. Abbreviations for growth factors: SCF, stem cell factor; FLT3L, FLT3 ligand; IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; EPO, erythropoietin; TPO, thrombopoietin.

IL3, GM-CSF, G-CSF T IL2 IL3 SCF IL7 GM-CSF GFU- FTL3L G-CSF G IL7 IL3 M-CSF IL6 B GM-CSF M-CSF SCF CLP IL2 GFU- GFU- GM M NK

MDC SCF

LDC IL3 IL5 HSC SCF SCF FLT3L CFU- IL3 SCF Eo PSC IL4 IL3 IL3 IL6 IL6 IL4 GM-CSF SCF GM-CSF CFU- Baso IL3 IL4 SCF CMP CFU- Mast IL3,SCF, IL3, GM-CSF GM-CSF IL11,EPO IL11,EPO

Bi-, tri- and BFU-E CFU-E multipotent progenitors

BFU- CFU- Mega Mega

SCF, SCF, IL1, IL3, IL3, IL6, IL6, GM-CSF, IL9, IL11, G-CSF, TPO GM-CSF, TPO Lineage committed progenitors HAE-H 01/13/2005 05:12PM Page 123

hemighost 123

Figure 42 Helper T cell. A diagrammatic representation of the interaction between a helper T cell and a B cell. The B cell binds an exogenous antigen, by means of its membrane immunoglobulin–CD79a complex, and processes it to a peptide which it presents, in a groove of an HLA type II molecule, to a helper T cell. The peptide, in its HLA type II context, is recognized by the CD3–T cell receptor (TCR)–CD4 complex. Other specialized antigen-presenting cells (e.g. macrophages and dendritic cells) can similarly present processed antigen to helper T cells. Binding of the helper T cell to the B cell also involves binding of CD2 on the T cell to CD58 on the B cell. CD54 is up- regulated on activated B cells and binds to CD11a/CD18 on T cells. In addition, there is binding of CD28 on the T cell to CD80 or CD86 on the B cell, giving stimulatory signals, or binding of CD152 to CD80 or CD86 on the B cell, giving inhibitory signals. CD154 (CD40 ligand) on the T cell binds to CD40 on the B cell, giving signals for somatic hypermutation and immunoglobulin class switching. Signalling is bidirectional. The B cell signals to the helper T cell to become activated and proliferate while the T cell signals to the B cell to mature into a plasma cell and switch from secreting IgM to secreting other classes of immunoglobulin. The progeny of the helper T cell that has been activated by an antigen-presenting B cell can migrate to other tissues where they initiate a cytotoxic or inﬂammatory response if they encounter target cells expressing the appropriate antigen.

Antigen-presenting and antibody-secreting B cell SmIg

Ag Antigen internalized, CD79 processed and presented

HLA CD80 or CD80 or type II CD54 CD58 CD40 CD86 CD86

CD11a/ CD2 CD28 CD152 CD154 CD3 TCR CD4 CD18 αβ

Helper T cell

Antigen (ag) Surface membrane immunoglobulin (SmIg)

CD79 Processed antigen

molecule; each immunoglobulin molecule helix–loop–helix see bHLH has two light chains (κ or λ) and two heavy HELLP syndrome a syndrome occurring chains (γ, α, µ, ε or δ) in pregnancy comprising Haemolysis, heavy chain disease a lymphoprolifer- Elevated Liver enzymes and Low ative disorder or plasma cell dyscrasia in Platelets which there is synthesis of heavy chain helper T cell a T lymphocyte that pro- (γ, α or µ) rather than synthesis of com- motes antigen secretion by B lympho- plete immunoglobulin molecules cytes (see type 1 and type 2 helper T cell) Heinz body an erythrocyte inclusion (Fig. 42) composed of denatured haemoglobin, hemighost an erythrocyte in which all detected by exposure to vital dyes such the haemoglobin appears retracted into as methyl violet one half of the cell leaving the remainder HAE-H 01/13/2005 05:12PM Page 124

124 hemizygosity

of the cell as an empty membrane; and elevated serum ferritin without any hemighosts are characteristic of oxidant elevation of serum iron concentration or damage and the presence of an unstable any tissue iron overload; the cataracts haemoglobin may be congenital or may develop during hemizygosity having a single copy of childhood or adult life; the underlying a gene on a single X chromosome, e.g. defect is in synthesis of L type ferritin, hemizygosity for G6PD deficiency which is increased and poorly regulated hemizygote an individual having one as a result of a mutation affecting the copy of a gene on a single X chromosome, iron-responsive element of L ferritin e.g. a male with a singe copy of a mutant mRNA; serum ferritin is L type rather G6PD gene than a mixture of L and H. HEMPAS Hereditary Erythroid Multi- hereditary persistence of fetal nuclearity with Positive Acidified Serum haemoglobin an inherited condition test—type II congenital dyserythropoietic in which fetal haemoglobin persists at anaemia (see acid lysis test) higher than normal levels beyond the heparin a sulphated glycosaminoglycan, neonatal period a naturally occurring anticoagulant in hereditary pyropoikilocytosis an human and animal tissues, which inhibits inherited abnormality of the erythrocyte thrombin, factor Xa and activated intrin- membrane leading to striking poikilo- sic pathway coagulation factors in vivo cytosis and severe haemolytic anaemia, and in vitro; as a therapeutic product, usually consequent on inheritance of it has usually been extracted from pig two different elliptogenic mutations or intestines (see also low molecular weight an elliptogenic mutation and a common heparin and unfractionated heparin) low expression allele, α spectrinLELY hepatitis inflammation of the liver hereditary spherocytosis an inherited hepatomegaly enlargement of the liver abnormality of the erythrocyte membrane HER2 see ERBB2 leading to spherical red cells, compensated hereditary passed down from a parent, haemolysis and sometimes haemolytic usually by means of genes located on anaemia, resulting from mutations in chromosomes but occasionally by mito- ANK1, SPTA1, SPTB, EA1 or EPB42 chondrial genes genes hereditary elliptocytosis an inherited hereditary stomatocytosis an in- abnormality of the erythrocyte mem- herited abnormality of the erythrocyte brane leading to elliptical red cells, some- membrane leading to formation of bowl- times to haemolysis and occasionally to shaped cells, referred to as stomatocytes a haemolytic anaemia, resulting from (Fig. 43), and either compensated haemo- mutations in the SPTA1, SPTB, AE1 or lysis or haemolytic anaemia EPB41 genes hereditary xerocytosis an inherited hereditary glucosyl ceramide lipidosis abnormality of the erythrocyte mem- see Gaucher’s disease brane leading to increased cation flux hereditary haemochromatosis a and either compensated haemolysis or hereditary condition leading to iron haemolytic anaemia overload; in adults, the condition usually Hermansky–Pudlak syndrome a results from mutation in the HFE gene heterogeneous inherited syndrome with but in a minority it results from mutation autosomal recessive inheritance char- in the TFR2 gene; the juvenile form acterized by oculocutaneous albinism results from mutation of a gene on chro- and defective platelet function, the latter mosome 1q resulting from a storage pool defect; hereditary hyperferritinaemia– some cases result from mutation of the cataract syndrome a constitutional HPS1 gene on chromosome 10; there is abnormality with autosomal dominant increased lipofuscin in bone marrow inheritance, characterized by cataracts macrophages HAE-H 01/13/2005 05:12PM Page 125

histidine-rich glycoprotein 125

Figure 43 Stomatocytes. it combines with transferrin receptor, Three stomatocytes, showing that in three reducing its affinity for iron; the C282Y dimensions a stomatocyte is bowl shaped. mutation, present in most patients with haemochromatosis, prevents the binding β of the HFE product to 2-microglobulin high grade a term used to describe aggressive, highly malignant lymphomas high hyperdiploid having between 51–60 chromosomes highly active antiretroviral therapy (HAART) triple-drug antiretroviral therapy for HIV infection employing a combination of drugs from three classes: (i) nucleoside-analogue reverse- transcriptase inhibitors, non-nucleoside- herpesviruses a group of viruses includ- analogue reverse-transcriptase inhibitors ing chicken pox/varicella, the Epstein– and protease inhibitors Barr virus and cytomegalovirus high performance liquid chromatog- herpes zoster shingles, recrudescence raphy (HPLC) a method of separating of varicella-zoster virus infection, causing proteins, such as haemoglobin variants, a vesicular rash in the distribution of a from each other on the basis of char- peripheral nerve acteristics such as size, hydrophobicity heterochromatin condensed, genetically and ionic strength; a solution of proteins inactive chromatin is passed through a specially designed heterodimer a dimer composed of two column with different proteins emerging dissimilar polypeptide chains after a characteristic period of time, refer- heterogeneous irregularly distributed red to as the retention time (Fig. 44) heterophile antibody an antibody HIP a gene, Huntingtin Interacting recognizing antigens on cells of another Protein 1, gene map locus 7q11.2; encodes species a protein which interacts with Huntingtin heteroplasmy the presence in a cell of and F-actin, and is involved in dopamine mutated and non-mutated mitochondrial receptor endocytosis at clathrin coated pits; DNA Huntingtin is the product of the gene that heterozygote an individual who has a is mutated in Huntington’s disease; HIP single copy of a specified autosomal or contributes to the HIP1-PDGFRB fusion (in a female) X chromosome gene gene in chronic myelomonocytic leuk- heterozygous having a single copy of a aemia associated with t(5;7)(q33;q11.2); specified autosomal or (in a female) X in the resulting fusion protein the chromosome gene extracellular domains of PDGFRβ are hexokinase an enzyme in the erythro- replaced with almost the entire HIP1 cyte glycolytic pathway (see Fig. 33, p. 113) molecule, leading to constitutive receptor HFE a gene on chromosome 6, mutation oligomerization and activation. of which can cause hereditary haemochro- hirudin an antithrombotic substance pro- matosis in homozygotes and compound duced in the salivary glands of the medicinal heterozygotes; previously known as HLA- leech, Hirudo medicinalis; recombinant H; it encodes a protein that interacts with forms are desirudin and lepirudin the transferrin receptor (product of the histamine an inflammatory mediator TFRC gene), negatively affecting cellular secreted by mast cells and basophils iron uptake from transferrin; the HFE histidine-rich glycoprotein a plasma β protein binds to 2-microglobulin, bind- protein, synthesized by platelets, that ing being essential for transport of the binds to plasminogen, thus reducing the HFE product to the cell surface where amount of circulating plasminogen avail- HAE-H 01/13/2005 05:12PM Page 126

126 histiocyte

Figure 44 High performance liquid chromatography. Separation of normal haemoglobins from each other by high performance liquid chromatography (HPLC): (a) normal adult showing, from left to right, haemoglobin F (shaded), glycosylated haemoglobin (long black arrow), haemoglobin A that has undergone post-translational modiﬁcation (short black arrow), haemoglobin

A (hollow arrow) and haemoglobin A2 (shaded); (b) premature baby showing, from left to right, haemoglobin F which has undergone post-translational modiﬁcation (short arrows), haemoglobin F (shaded), and haemoglobin A (hollow arrow); note

that in this premature baby there is negligible haemoglobin A2.

45.0

37.5

30.0

22.5 % 1.22 1.30 15.0 3.61 1.09 7.5 1.68 F A2 2.50 0.0

0 123456 (a) Time (min)

0.125

0.100 2.50 0.075 0.95 Volts 0.050

0.025

0.000 F – 1.18 0.00 0.75 1.50 2.25 3.00 3.75 4.50 5.25

(b) Time (min)

able for conversion to plasmin; it there- and related lineages are designated in the fore has an antifibrinolytic effect and WHO classification as shown in Table 6 deficiency, which is very rare, is asso- histiocytic lymphoma an outmoded ciated with an increased likelihood of designation of large cell lymphoma of thrombosis B- or T-lymphocyte lineage rather than histiocyte an alternative designation of of histiocyte lineage; to avoid confusion, a macrophage; neoplasms of histiocytic a tumour resembling a lymphoma but HAE-H 01/13/2005 05:12PM Page 127

hMRE11 127

Table 6 The WHO classiﬁcation of histiocytic and dendritic cell neoplasms.

Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Interdigitating dendritic cell sarcoma/tumour Follicular dendritic cell sarcoma/tumour Dendritic cell sarcoma, not otherwise classiﬁed

composed of histiocytes should be referred genes that regulate the transcription of to as a ‘histiocytic sarcoma’ (see Table 6) type II HLA genes: either the transactiva- histiocytic medullary reticulosis a tor gene, CIITA at 16p13, or transcrip- disease characterized by infiltration of tion factor genes—RFXAP on 13q, RFX5 tissues including the bone marrow by at 1q21 or RFXANK; numbers of CD4+ strikingly haemophagocytic histiocytes; T cells are greatly reduced once thought to be a histiocyte malign- HLF a gene, Hepatic Leukaemic Factor, ancy, it is now known that at least the gene map locus 17q21-22, encodes a majority of cases are reactive leucine zipper transcription factor which histiocytosis increased macrophages in is normally expressed in liver, kidney bone marrow or other tissues and neurones within the central nervous histiocytosis X a former designation of system; HLF contributes to the E2A- Langerhans cell histiocytosis, a neoplasm HLF fusion gene in B-lineage acute lym- of Langerhans cells (see Table 6) phoblastic leukaemia associated with histogram a graphical representation of t(17;19)(q21-22;p13); two different rear- the distribution of measurements using rangements between E2A and HLF are rectangular bars to represent the relative known; in each case, the chimeric protein frequency of a certain measured value comprises the amino-terminal transact- (Fig. 45) ivation domain of E2A (TCF3) and the histology the study of the structure of carboxyl-terminal leucine zipper dimer- tissues by examination of stained tissue ization domain of HLF; both fusion sections proteins induce expression of the zinc histones proteins bound to DNA in finger transcriptional repressor slug, chromosomes which in turn down-regulates the ex- histoplasmosis a disease caused by infec- pression of pro-apoptotic proteins tion by the fungus, Histoplasma capsulatum HLXB9 homeobox gene HB9, gene map HIV the human immunodeficiency virus locus 7q36, encodes a homeobox tran- HLA a complex of genes at 6p21.3 encoding scription factor which is expressed in the α chain of class I HLA antigens and the CD34+ but not in CD34− bone marrow α and β chains of class II HLA molecules cells and is down-regulated during line- HLA human leucocyte antigen age commitment; HLXB9 contributes to HLA type I deficiency an immune an HLXB9-ETV6 fusion gene in infants deficiency syndrome (see bare lymphocyte with acute myeloid leukaemia associated syndrome) in which a mutation in either with t(7;12)(q36;p13); germline muta- the TAP1 or TAP2 genes at 6p21.3 means tions in this gene are associated with the that there is defective delivery of peptides currarino triad (sacral agenesis, ureteric to developing type I HLA molecules, and perianal dysgenesis) which are therefore unstable and are not hMRE11 a gene, gene map locus 11q21; efficiently transported to the cell surface encodes a DNA repair enzyme expressed HLA type II deficiency an immune in all proliferating cells; hMRE11 is deficiency syndrome (see bare lymphocyte mutated in ataxia-telangiectasia-like syndrome) resulting from a mutation in disorder HAE-H 01/13/2005 05:12PM Page 128

128 Hodgkin’s cell

Figure 45 Histograms.

Two histograms showing the distribution of serum vitamin B12 concentrations in 80 healthy volunteers: (a) plotted on an arithmetic scale, showing that the distribution is not Gaussian; (b) re-plotted on a logarithmic scale, showing that the distribution of the data is now Gaussian, i.e. the data have a log normal distribution.

8 Std dev = 117.38 Mean = 298.5 n = 80 6

0 100 150 200 250 300 350 400 450 500 550 600 650

(a) ACB12

20 Std dev = 0.17 Mean = 2.44 n = 80

0 2.00 2.06 2.13 2.19 2.25 2.31 2.38 2.44 2.50 2.56 2.63 2.69 2.75 2.81 (b) LOGACB12

Hodgkin’s cell a mononuclear giant cell and mononuclear Hodgkin’s cells in an with a large nucleolus that is part of appropriate background of lymphocytes, the neoplastic population in Hodgkin’s eosinophils and fibroblasts with variable disease collagen fibrosis; the neoplastic cells are Hodgkin’s disease or Hodgkin lym- almost always B lymphocytes (but in 1–2% phoma a lymphoma characterized by of patients are T lymphocytes); desig- certain histological features, specifically nated in the WHO classification as shown by the presence of Reed–Sternberg cells in Table 7, the disease characteristically HAE-H 01/13/2005 05:12PM Page 129

HOX11L2 129

Table 7 The WHO classiﬁcation of Hodgkin Lymphoma (Hodgkin’s disease).

Nodular lymphocyte-predominant Hodgkin lymphoma Classical Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma Lymphocyte-depleted classical Hodgkin lymphoma

presents with enlargement of lymph nodes host the recipient of a transplant (or an (see Figs 61 and 70, pp. 188 and 210) individual harbouring a parasite) hof a German term indicating the hollow Howell–Jolly body a nuclear inclusion in a nucleus in which the Golgi apparatus in an erythrocyte is located Howship’s lacuna a hollow on the homeobox a DNA binding domain surface of a bony spicule occupied by characteristic of a family of transcription an osteoclast factors that included PBX1 and HOX11; HOX genes genes encoding a superfam- see also HOX genes ily of evolutionarily conserved transcrip- homeodomain see HOX genes tion factors which share a 60 amino-acid homocysteine an amino acid, increased DNA-binding domain, the homeodomain; plasma levels of which, whether inherited they fall into two classes—I and II; class or acquired in origin, are associated with I genes are organized into 4 clusters an increased thrombotic risk (A,B,C,D) located on chromosomes 7, homodimer a dimer with two identical 17, 12 and 2 respectively; class II genes chains are dispersed throughout the genome homogeneous evenly distributed and may have divergent homeodomain homogeneously staining region (hsr) sequences; clusters B and C play a role in a segment of a chromosome that stains erythropoiesis, whilst members of cluster homogeneously, indicating ampliﬁcation A are predominantly expressed in cells of of DNA sequences granulocytic lineage; virtually all HOX homologous structurally similar, in some genes of the A, B and C clusters are ex- circumstances suggesting a common origin pressed in pluripotent haemopoietic stem in the remote past (e.g. homologous genes cells—a feature lost with the onset of in different species) lineage commitment; several non-cluster homologous chromosomes a matching HOX genes are also important in normal pair of chromosomes, one derived from haemopoiesis each parent of the individual HOX11 a gene, Homeobox 11, also homology having structural similarity known as T-Cell Leukaemia 3, TCL3, homotypic having the same nature, e.g. and TLX1; gene map locus 10q24, which homotypic adhesion is adhesion of cells encodes a non-cluster homeobox tran- to other cells of the same type scription factor which is thought to play a homozygous having identical alleles at role in splanchnic development; HOX11 a given locus is dysregulated: hookworm a parasitic intestinal round • by proximity to the TCRAD (αδ) locus worm which may cause eosinophilia and in T-lineage acute lymphoblastic leuk- iron deﬁciency anaemia aemia associated with t(10;14)(q24;q11) hormone a long distance chemical • by proximity to the TCRB gene at 7q35 mediator in T-lineage acute lymphoblastic leuk- horned cell a keratocyte, an erythrocyte aemia associated with t(7;10)(q35;q24) with two or four symmetrical spicules HOX11L2 a gene, Homeobox 11-Like 2, (see Fig. 50, p. 147) also known as T-cell Leukaemia homeobox HAE-H 01/13/2005 05:12PM Page 130

130 HOXA9

3 (TLX3), and Respiratory Neurone HPA human platelet antigen homeobox (RNX); gene map locus 5q35.1; HPLC high performance liquid chromato- encodes a non-cluster homeobox tran- graphy (previously ‘high pressure liquid scription factor which is thought to play a chromatography’) role in the development of the medulla HPRT an X chromosome gene encoding oblongata; is transcriptionally activated, hypoxanthine-guanine phosphoribosyl- probably by proximity to the transcrip- transferase, mutation of which can con- tion regulatory elements of BCL11B, in vey resistance to 6-thioguanine therapy; a quite common t(5;14)(q35;q32) cryptic it is sometimes used for clonality studies translocation in T-acute lymphoblastic HSP89A a gene, Heat Shock Protein 89 leukaemia Alpha, gene map locus unknown, encodes HOXA9 a gene, Homeobox A9; gene map heat shock protein 89α; the gene con- locus 7p15-p14.2, encodes a class I home- tributed to an HSP89A-BCL6 fusion gene obox transcription factor that is thought in a high grade gastric B-cell lymphoma to be important in myeloid differentia- hsr a cytogenetic abbreviation indicating tion; HOXA9 contributes to the NUP98- a homogeneously staining region HOXA9 fusion gene in M2 acute myeloid HTLV-I human T-cell lymphotropic virus I leukaemia associated with t(7;11)(p15;p15) HTLV-I-associated myelopathy (HAM) (see also NUP98); the fusion protein func- a myelopathy caused by HTLV-I, the tions as a transcription factor; in acute retrovirus which also causes adult T-cell myeloid leukaemia HOXA9 expression leukaemia/lymphoma correlates strongly with a worse prognosis hTR the gene encoding telomerase RNA, HOXA11 a gene, Homeobox A11, mutation of which can lead to autosomal gene map locus 7p15-p14.2, encodes a dominant dyskeratosis congenita class I homeobox transcription factor human herpesvirus 8 (HHV8) a her- that is important in myeloid differentia- pesvirus that has an aetiological role in tion; contributed to a NUP98-HOXA11 primary effusion lymphoma and Cattleman’s fusion gene in a patient with Ph-negative disease chronic myeloid leukaemia transforming human immunodeficiency virus (HIV) rapidly to M2 acute myeloid leukaemia; the retrovirus that causes the acquired germline mutations in the homeodomain immune deficiency syndrome (AIDS) of HOXA11 are seen in radioulnar synos- human leucocyte antigen (HLA) a tosis in association with amegakaryocytic group of highly polymorphic cell surface thrombocytopenia. antigens, encoded by genes at 6p21.3, HOXD13 a gene, Homeobox D13, involved in self and non-self recogn- also known as HOX4I, gene map locus ition, tolerance, rejection of allografts 2q31-q32, encodes a class I homeobox and graft-versus-host disease, divided transcription factor that is not normally into HLA class I, class II and class III expressed in haemopoietic tissues; it con- antigens tributes to a NUP98-HOXD13 fusion gene, human leucocyte antigens, class I one of two fusion genes present in therapy- (HLA class I) molecules that are related and de novo acute myeloid leuk- mainly involved in the presentation of aemia associated with t(2;11)(q31;p15); endogenous antigen-derived peptides to germline mutations in this gene are CD8+ cytotoxic T cells and NK cells; associated with synpolydactyly with expressed on most somatic cells but to a foot anomalies varying degree; expressed on all leuco- Hoyerall–Hreidarsson syndrome a cytes and on platelets but negative or syndrome of aplastic anaemia, immun- weakly expressed on erythrocytes; com- odeficiency, microcephaly and cerebellar posed of a heavy chain that is encoded hypoplasia resulting from a mutation in by genes at 6p21.3 and a common light the DKC1 gene; a severe variant of X- chain, β2 microglobulin, which is encoded linked dyskeratosis congenita by a gene on chromosome 15; there are HAE-H 01/13/2005 05:12PM Page 131

human T-cell lymphotropic virus I (HTLV-I) 131

Table 8 Human neutrophil antigens – recommended terminology and the proteins on which they are expressed.

System Antigen Protein on which antigen is located

HNA-1 HNA-1a (previously NA1) FcγRIII (CD16) HNA-1b (previously NA2) HNA-1c (previously SH) HNA-2 HNA-2a (previously NB1) Gp58–64, a GPI-linked glycoprotein HNA-3 HNA-3a (previously5b) Gp70–95 HNA-4 HNA-4a (previously MART) CD11b HNA-5 HNA-5a (previously CND) CD11a

Table 9 Human platelet antigens – recommended terminology and the platelet glycoproteins on which they are expressed.

System Antigens Glycoprotein on which antigens are carried

HPA-1 HPA-1a (previously PlA1, Zwa) IIIa HPA-1b (previously PlA2, Zwb) HPA-2 HPA-2a (previously Kob)Ibα HPA-2b (previously Koa, Siba) HPA-3 HPA-3a (previously Baka, Leka) IIb HPA-3b (previously Bakb) HPA-4 HPA-4a (previously Yukb, Pena) IIIa HPA-4b (previously Yuka, Penb) HPA-5 HPA-5a (previously Brb, Zavb)Ia HPA-5b (previously Bra, Zava, Hca) HPA-6w HPA-6bw (previously Caa, Tua) IIIa HPA-7w HPA-7bw (previously Mo) IIIa HPA-8w HPA-8bw (previously Sra) IIIa HPA-9w HPA-9bw (previously Maxa) IIb HPA-10w HPA-10bw (previously Laa) IIIa HPA-11w HPA-11bw (previously Groa) IIIa HPA-12w HPA-12bw (previously Iya)Ibβ HPA-13w HPA-13bw (previously Sita) GP1a

three classical HLA class I groups of anti- genes at 6p21.3, falling into HLA-DM, gens (HLA-A, HLA-B and HLA-C) and HLA-DO, HLA-DP, HLA-DQ and three non-classical (HLA-D, HLA-E and HLA-DR groups HLA-F) human neutrophil antigen (HNA) human leucocyte antigens, class II neutrophil-speciﬁc alloantigens encoded (HLA class II) molecules that are by genes at 5 loci (Table 8) mainly involved in the presentation of human platelet antigen (HPA) exogenous antigen-derived peptides to platelet-speciﬁc alloantigens encoded by CD4+ helper T cells; expressed on B genes found at at least 13 loci; the ISBT cells, activated T cells, monocytes, has agreed a standardized nomenclature macrophages, dendritic cells, activated (Table 9) neutrophils and thymic epithelium; class human T-cell lymphotropic virus I II antigens are heterodimers encoded by (HTLV-I) a retrovirus that causes adult HAE-H 01/13/2005 05:12PM Page 132

132 humoral immunity

T-cell leukaemia/lymphoma and HTLV- cells (ii) increased staining of nuclei, con- I-associated myelopathy sequent on altered chromatin structure humoral immunity antibody-mediated hyperchylomicronaemia increased immunity plasma concentration of chylomicrons HUT11 a locus at 18q12-q21 where vari- hyperdiploid having more than 46 ous alleles encode antigens of the Kidd chromosomes blood group antigen system which also hyperendemic constantly present in a function as the human erythroid urea community and having a high prevalence transporter; genes at this locus are the hypereosinophilic syndrome a syn- codominant Jka and Jkb and various Jk drome of cardiac and other tissue dam- null alleles that result from mutation of age resulting from an increased eosinophil the wild type Jka or Jkb; a Jk(a-b-) count with tissue damage consequent on phenotype (rare except in Finns and the release of eosinophil granule contents Polynesians) can result from homozygos- (see idiopathic hypereosinophilic syndrome) ity or compound heterozygosity for Jk hyperferritinaemia with congenital null alleles or from inheritance of the cataracts see hereditary hyperferriti- dominant unlinked In inhibitor gene, naemia-cataract syndrome In(JK) hypergammaglobulinaemia hyalomere the agranular periphery of a increased concentration of serum platelet immunoglobulins hybridization the annealing of comple- hypergranular promyelocytic leuk- mentary sequences of DNA or RNA, e.g. aemia acute myeloid leukaemia with Southern and Northern blotting arrest of maturation at the promyelocyte hybridoma a clone of cells capable of stage with the promyelocytes being producing a monoclonal antibody, hypergranular produced by fusion of an antibody- hyperhomocysteinaemia an inherited producing cell with a mouse myeloma cell metabolic defect resulting from deﬁciency hydrops fetalis severe oedema and of cystathionine β-synthase, associated serous effusions in a fetus or neonate; with an increased risk of thrombosis may be caused by severe anaemia, as in hyperimmunoglobulin D syndrome haemoglobin Bart’s hydrops fetalis, severe an autosomal recessive condition, resulting haemolytic disease of the newborn and from mutation in the mevalonate kinase intrauterine parvovirus B19 infection gene, characterized by periodic fever with hydroxocobalamin the form of vitamin leucocytosis and an acute phase response

B12 used for therapy hyperimmunoglobulin E syndrome hydroxyurea an antimetabolite used to a congenital immunodeficiency syndrome treat chronic myeloid leukaemias and characterized by abscesses, osteopenia, myeloproliferative disorders eosinophilia and unusual facial features; hyperbetalipoproteinaemia it maps to chromosome 4 increased concentration of plasma beta hyperimmunoglobulin M syndrome lipoproteins either (i) an X-linked immune deficiency hyperbilirubinaemia increased plasma syndrome in which a mutation in the gene bilirubin concentration at Xq26.3-27.1 encoding CD154 results in hypercalcaemia increased plasma cal- failure of helper T-cells to express CD154: cium concentration helper T cells therefore cannot bind to hypercholesterolaemia increased CD40 on antigen-presenting B cells (see serum cholesterol concentration Fig. 42, p. 123), leading to a failure of class hyperchromatic showing increased up- switching and susceptibility to cancer and take of stain, thus appearing dense autoimmune disease or (ii) an autosomal hyperchromia (i) increased staining of recessive syndrome, some cases resulting red cells reflecting an increased haemo- from mutation in the activation-induced globin concentration within individual red cytidine deaminase gene at 12p13, an HAE-H 01/13/2005 05:12PM Page 133

hypoxia 133

mRNA-editing enzyme, with resultant naemia or, less often, from a marked IgG and IgA deﬁciency with normal or increased in polyclonal immunoglobulins elevated IgM hyphaema bleeding into the anterior hyperkalaemia increased plasma potas- chamber of the eye sium concentration hypochromia reduced staining of hyperlipaemia increased concentration erythrocytes of blood lipids hypodiploid having fewer than 46 but hypermutation see somatic hypermutation more than 23 chromosomes hypernatraemia increased plasma hypogranular neutrophil neutrophil sodium concentration with reduced secondary granules hyperparathyroidism increased activ- hypogranular variant of promyelo- ity of the parathyroid glands cytic leukaemia a variant form of hyperplasia increase of the number of hypergranular promyelocytic leukaemia cells of a certain lineage or tissue in which the leukaemic promyelocytes hyperreactive malarial splenomegaly appear hypogranular rather than hyper- splenomegaly and increased polyclonal granular; the leukaemic cells have char- IgM as a consequence of chronic malaria, acteristic bilobed nuclei previously referred to as tropical hyponatraemia reduced plasma sodium splenomegaly concentration hypersplenism splenomegaly leading to hypoparathyroidism reduced activity pancytopenia as a consequence of pool- of the parathyroid glands ing of cells in the spleen and a decreased hypoplasia underdevelopment or regres- erythrocyte lifespan sion of an organ, tissue or cell lineage hypertension increase of blood pressure hypoplastic acute myeloid leukaemia hyperthyroidism overactivity of the acute myeloid leukaemia that is unusual thyroid gland in that the bone marrow is hypocellular hypertonic having an osmolarity greater rather than hypercellular than normal; more concentrated than hypoplastic anaemia an anaemia, normal usually pancytopenia, as a consequence hypertrophy overdevelopment of an of bone marrow hypoplasia; usually part organ or tissue; increased size rather than of the spectrum of aplastic anaemia increased number of cells hypopyon accumulation of leucocytes hyperuricaemia increased serum uric in the anterior chamber of the eye, a rare acid concentration complication of leukaemia hyperviscosity a pathological increase hyposplenism reduced or absent in the viscosity of the blood or plasma, splenic function may be a feature of multiple myeloma or hypothyroidism reduced activity of the Waldenström’s macroglobulinaemia thyroid gland hyperviscosity syndrome a clinical hypotonic having an osmolarity less syndrome resulting from hyperviscosity; than normal; more dilute than normal clinical features may include mental hypoventilation reduced breathing changes and reduced level of conscious- hypoxanthine-guanine phosphoribo- ness, visual changes resulting from effects syltransferase a purine salvage on the retina, congestive cardiac failure enzyme encoded by HPRT and bleeding; may result from multiple hypoxia inadequate supply of oxygen to myeloma or Waldenström’s macroglobuli- cells HAE-I 01/13/2005 05:12PM Page 134

i an antigen composed of repeats of linear are more likely to be designated, for ex- poly-N-acetyllactosaminoglycan, expres- ample, ‘post-polycythaemia myelofibrosis’) sed on fetal red cells, in adults largely idiopathic thrombocytopenic pur- converted to the I antigen, branched pura (ITP) a previous designation of poly-N-acetyllactosaminoglycan, by the autoimmune thrombocytopenic purpura action of β-1,6-N acetylglucosaminyl idiotype the specific surface antigens transferase which permit a clone of lymphocytes or i (or iso) an isochromosome plasma cells to be recognized, dependent i phenotype the null phenotype of the I on the specific immunoglobulin which is blood group, resulting from deletion or expressed on the surface membrane mutation of the IgnT gene, in Asians Ig immunoglobulin, e.g. IgG, IgA, IgM, associated with congenital cataract IgE or IgD I an antigen composed of repeats of IGH the Immunoglobulin Heavy chain branched poly-N-acetyllactosaminoglycan, locus, at 14q32 encoding the heavy chains on adult red cells, produced by the action of immunoglobulin; there are multiple V of β-1,6-N acetylglucosaminyl transferase (variable), D (diversity), J (joining) and C on i antigen (constant) gene segments; rearrangement I-branching β-1,6-N acetylglucosaminyl of gene segments at the IGH locus occurs, transferase an enzyme encoded by producing a gene encoding a specific the I or IgnT gene at 9q21, which converts heavy chain (Fig. 46); the IGH enhancer the i antigen to the I antigen can contribute to oncogenesis by dysreg- I cell disease a congenital metabolic ulating many other genes such as BCL2, disorder, associated with vacuolated BCL3, BCL6, BCL7A, BCL8, BCL9, lymphocytes BCL10, BCL11A, CDK6, C4ST1, Cyclin ICSH International Council (previously D1, Cyclin D2, FCγRIIB, FGFR3, IL3, Committee) for Standardization in IRF4, MMSET, MAF, MUM2, MUM3, Haematology MYC, NF-κB2, PAFAH2, PAX5 and idiopathic literally ‘of unknown cause’ RCK. but the term often continues in use long IGK the locus at 2p12 encoding the κ light after the cause of a disorder is known chain of immunoglobulin idiopathic hypereosinophilic syn- IGL the locus at 22q11 encoding the λ drome a syndrome defined as a hyper- light chain of immunoglobulin eosinophilia of unknown cause, persisting IKAROS a gene, also known as Zinc for at least six months and with associ- Finger protein, subfamily 1A, member 1, ated tissue damage ZNFN1A1, gene map locus 7p13-p11.2, idiopathic myelofibrosis bone marrow encodes the archetypal member of a fam- fibrosis consequent on a chronic myelo- ily of lymphoid-restricted zinc finger proliferative disorder (but conventionally transcription factors that are considered excluding cases following polycythaemia, master regulators of lymphocyte differen- rubra vera, essential thrombocythaemia tiation; there are at least 8 alternatively and chronic granulocytic leukaemia, which spliced transcripts encoding isoforms with

134 HAE-I 01/13/2005 05:12PM Page 135

IKAROS 135

Figure 46 The IGH locus and the generation of antigen receptor diversity. Antigen receptors for B cells (immunoglobulins, Igs) and T cells (T cell receptors, TCRs) are heterodimers in which each polypeptide is composed of an amino terminal variable (V) region joined to a constant (C) region. Ig and TCR genes are similar in organization and permit the generation of proteins with V domains that are unique to the cells that make them. The V domains of IgH chains (and TCR β or δ chains) are encoded by a α γ combination of VH, D and J segments; the partner polypeptide (Ig light chains or TCR or ) is assembled from V and J segments only. There are a few hundred such segments at the IGH locus (and a similar number at each Ig light chain locus) and of these, about 30% are pseudogenes; yet it is estimated that the total diversity for human immunoglobulins is 1014. Two strategies allow for the generation of such huge diversity from so few genes: (i) T and B cells use a site-specific DNA recombination mechanism called V(D)J recombination to assemble a V region gene from germ line DNA by cutting and joining together randomly chosen combinations of one of each of the segments. The intervening DNA is excised and lost from the genome of the mature lymphocyte. This process is catalysed by RAG proteins (encoded by Recombination Activating Genes) which recognize recombination signal sequences (RSSs) flanking each segment. The RSSs ensure the correct order of V(D)J recombination is followed and prevent V–V or D–D joining. The recombination process is imprecise and leads to small deletions and random insertions (*) at the V–D and D–J junctions of functional IGH loci, adding additional diversity. (ii) Mature B cells exhibit the phenomenon of somatic hypermutation, whereby random single base changes are directed to gene segments encoding antigen binding pockets in rearranged VDJ genes (s). This may either increase or decrease the specificity of the expressed Ig for its antigen. The mechanism of this process is obscure. (iii) In the case of IGH genes, the same V region can be joined to several different C regions in the descendants of an original B cell (isotype or class switching), so permitting the same antigen specificity to be utilized in different biological contexts. The mechanism of this is unclear.

VH D J Constant regions segments segments segments ~300 ~20 6 µδγγ ψεα ψγ γ γ ε α 3 1 1 2 4 2 Germline IgH locus

Cleavage and religation

Small deletions, random insertions palindromic additions

* Functional IgH locus *

Somatic hypermutation HAE-I 01/13/2005 05:12PM Page 136

136 IL

common N-terminal and C-terminal Factor 2, BSF2; gene map locus 7p21; domains (Ik1 through Ik8); an in-frame encodes interleukin-6 deletion of 10 amino acids upstream of IL7 a gene, Interleukin-7, gene map locus the transcription activation domain and 8q12-q13, encodes interleukin-7 adjacent to the C-terminal zinc ﬁngers IL8 a gene, Interleukin-8, also known of Ik-2, Ik-4, Ik-7, and Ik-8 has been as chemokine ligand 8, CXCL8 and reported in childhood acute lymphoblas- Neutrophil-Activating Peptide 1, NAP1; tic leukaemia; IKAROS fuses to BCL6 as gene map locus 4q12-q13; encodes a result of the t(3;7)(q27;p12) transloca- interleukin-8 tion in diffuse large B-cell lymphoma; IL9 a gene, Interleukin-9, also known as IKAROS mutations and decreased activ- T-cell/mast cell growth factor P40, gene ity are associated with disease progres- map locus 5q31.1, encodes interleukin-9 sion in chronic granulocytic leukaemia IL10 a gene, Interleukin-10, also known IL interleukin as Cytokine Synthesis Inhibitory Factor, IL1A, IL1B two genes, gene map locus CSIF, gene map locus 1q31-q32, encodes 2q14, encoding Interleukin-1α (acidic) interleukin-10 and Interleukin-1β (neutral); a TATA IL11 a gene, Interleukin-11, gene map locus box mutation in the IL1B promoter is 19q13.3-13.4, encodes interleukin-11 associated with an increased risk of IL12A a gene, Interleukin-12 Alpha hypochlorhydria and gastric cancer after chain, encodes p35 subunit of interleukin- H. pylori infection 12, gene map locus 3p12-q13.2 IL2 a gene, Interleukin-2, also known as IL12B a gene, Interleukin-12 Beta chain, T-Cell Growth Factor, TCGF, gene map encodes p40 subunit of interleukin-12, locus 4q26-q27, encodes interleukin-2 gene map locus 5q31.1-q33.1 IL2RA a gene, Interleukin-2 Receptor IL13 a gene, Interleukin-13, gene map Alpha, gene map locus 22q11.2-q13, locus 5q31, encodes interleukin-13 encodes interleukin-2 receptor α, also IL14 a gene, Interleukin-14, gene map known as CD25 and Tac (Activated T cell) locus unknown, encodes interleukin-14 IL2RB a gene, Interleukin-2 Receptor IL15 a gene, Interleukin-15, gene map Beta, encodes interleukin-2 receptor β, locus 4q31, encodes interleukin-15 also known as CD122, gene map locus IL16 a gene, Interleukin-16, gene map 22q11.2-q13 locus 15q26.1, encodes interleukin-16 IL2RG a gene, Interleukin-2 Receptor IL17 a gene, Interleukin-17, gene map Gamma, gene map locus Xq13, encodes locus 2q31, encodes interleukin-17 interleukin-2 receptor γ, also known as IL18 a gene, Interleukin-18, gene map CD132 locus 11q22.2-q22.3, encodes interleukin- IL3 a gene, Interleukin-3, gene map locus 18 5q31, encodes interleukin-3; IL3 is dys- IL19 a gene, Interleukin-19, gene map regulated by proximity to the IGH locus locus 1q32, encodes interleukin-19 in acute lymphoblastic leukaemia asso- IL20 a gene, Interleukin-20, gene map ciated with t(5;14)(q31;q32) leading to locus 1q32, encodes interleukin-20 eosinophilia IL21R a gene, Interleukin-21 Receptor, IL4 a gene, Interleukin-4, also known as gene map locus 16p11, normally ex- B-cell Stimulatory Factor 1, BSF1; gene pressed by peripheral blood NK cells; map locus 5q31.1; encodes interleukin-4 contributes to a IL21R-BCL6 fusion gene IL5 a gene, Interleukin-5; also known in B-lineage non-Hodgkin’s lymphoma as Eosinophil Differentiation Factor, with t(3;16)(q27;p11) EDF; gene map locus 5q31.1; encodes ileum the distal small intestine, the site of

interleukin-5 maximum vitamin B12 absorption IL6 a gene, Interleukin-6, also known as iliac pertaining to the ilium interferon beta 2, Hepatocyte Stimula- ilium one of the bones of the pelvis; the tory Factor, HSF and B-cell Stimulatory posterior superior iliac spine, which is HAE-I 01/13/2005 05:12PM Page 137

immune system 137

Table 10 WHO classiﬁcation of B-cell neoplasms*.

Precursor B-cell neoplasms Precursor B lymphoblastic leukaemia/lymphoma Mature B-cell neoplasms B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma (morphological variant – µ heavy chain disease) B-cell prolymphocytic leukaemia Lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (morphological variant – γ heavy chain disease) Mantle cell lymphoma Splenic marginal zone lymphoma (including splenic lymphoma with villous lymphocyte) Hairy cell leukaemia (morphological variant – hairy cell variant leukaemia) Plasma cell myeloma Monoclonal gammopathy of undetermined signiﬁcance (MGUS) Solitary plasmacytoma of bone Extraosseous plasmacytoma Primary amyloidosis Heavy chain disease Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissues (MALT-lymphoma) Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma (morphological variants – blastoid variants and variants resembling small cell lymphoma and marginal zone B-cell lymphoma). Diffuse large B-cell lymphoma (morphological variants – centroblastic, immunoblastic, T-cell/histiocyte-rich, anaplastic, grade III lymphomatoid papulosis*) Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Burkitt lymphoma/leukaemia:

* In addition, two entities of ‘uncertain malignant potential’ are recognized: lymphomatoid granulomatosis and post-transplant lymphoproliferative disorder, polymorphic.

part of the ilium, is often used for bone immune complex disease a disease marrow aspiration and trephine biopsy caused by deposition of immune com- imatinib mesylate a speciﬁc inhibitor of plexes in tissues or on cells BCR-ABL tyrosine kinase and of platelet- immune deﬁciency inability to mount derived growth factor β, used in the treat- an adequate immune response ment of chronic granulocytic leukaemia immune haemolytic anaemia a and other chronic myeloid leukaemias haemolytic anaemia mediated by alloan- involving PDGFRB; imatinib mesylate tibodies, autoantibodies, drug-dependent was previously known as STI-571 autoantibodies or immune complexes immune (i) relating to the body’s immune phenotype see immunopheno- response to antigens, whether by anti- type body production or T-cell responses (ii) immune suppression suppression of able to mount a rapid and adequate immune responses by disease or by response to an antigenic stimulus; usually immunosuppressive therapy indicative of a secondary response to a immune system a system of molecules, previously encountered antigen cells and tissues involved in protection immune complex a complex of antigen against infection, permitting innate and and antibody acquired immune responses HAE-I 01/13/2005 05:12PM Page 138

138 immune tolerance

immune tolerance a state in which Figure 47 Immunofixation. autologous antigens do not provoke an Immunofixation to demonstrate the nature of a effective immune response paraprotein in a patient with multiple myeloma. immunity the body’s defence against Serum protein electrophoresis shows a discrete band in the early γ region (arrow head, top). foreign or abnormal material, e.g. invad- Immunofixation shows that the abnormal band ing micro-organisms; immune responses reacts with anti-γ and ant-λ antisera and it therefore are either specific, being mediated by represents an IgGλ paraprotein. Antisera to α, µ and cells that can recognize antigens, or non- κ show only normal polyclonal immunoglobulins. specific, e.g. mediated by complement in the absence of specific immune responses immunization the process by which immunity to various infections is promoted by exposure to altered or killed micro- organisms or antigens derived from them immunoblast a large transformed lymphocyte resulting from stimulation of a lymphocyte by an antigen or by a lectin such as phytohaemagglutinin; immunoblasts have a large central nucleolus and plentiful basophilic cytoplasm immunoblastic lymphoma a large cell lymphoma with lymphoma cells resembling immunoblasts, in the WHO classification regarded as a subtype of diffuse large B-cell lymphoma (see Table 10, p. 137) immunocytochemistry identification of antigens on cells by means of antibodies, the binding of which is recognized by means of a cytochemical reaction immunocytoma a neoplasm of cells showing some degree of plasma cell differentiation; lymphoplasmacytoid lymphoma in the WHO classification immunofixation a technique for characterizing paraproteins by means of electrophoresis followed by binding to a class-specific antibody (Fig. 47) protects against proteolysis; there are two immunofluorescence a method of re- subclasses (see Fig. 48) cognizing antigens by means of antibodies immunoglobulin D an immunoglo- bound to fluorochromes bulin with a δ heavy chain; as a cell sur- immunoglobulin a plasma or cell- face molecule on B lymphocytes it binds bound glycoprotein with antibody activity, antigens, probably leading to activation further categorized as immunoglobulin of the cell; as a plasma protein its physio- of five classes—G, A, M, E and D; each logical role is unknown immunoglobulin molecule has a basic immunoglobulin E an immunoglobulin structure of two identical heavy chains with an ε heavy chain, involved in defence and two identical light chains (Fig. 48) against parasitic infections and in allergic immunoglobulin A an immunoglobu- reactions lin with an α heavy chain, responsible immunoglobulin G an immunoglobulin for immunity at mucosal surfaces and with a γ heavy chain, of subtypes IgG1, present in secretions as a dimer with an IgG2, IgG3 and IgG4; responsible for additional secretory component that secondary immune responses (see Fig. 48) HAE-I 01/13/2005 05:12PM Page 139

impedance counter 139

Figure 48 Immunoglobulin molecules. (c) VH The structure of immunoglobulin molecules of IgG, C 1 VL H IgA and IgM classes. The basic structure is of two CL heavy (grey) and two light chains (black) with both C 2 the light chains and the heavy chains having a H CH3 variable region, which gives antibody speciﬁcity, and a constant region which conveys other CH4 properties, such as binding to complement or to Fc receptors on neutrophils and macrophages (a) the J IgG molecule has heavy chains with one variable regions and three constant regions; the two heavy chains are crosslinked and each light chain is crosslinked to a heavy chain; (b) the IgA molecule has a similar structure to the IgG molecule but is present in secretions as a dimer with the two monomers being joined by a J chain (crosshatched); in addition, epithelial cells add a secretory component (white); (c) the IgM is present in serum as a pentamer; ﬁve identical subunits are joined to each other and to a J chain. The heavy chain of the IgM molecule differs from that of the IgG and IgA immunoglobulin heavy chain gene molecules in that it has four rather than three a gene at the IGH locus encoding an constant regions. immunoglobulin heavy chain—γ, αµ, ε or δ (a) immunoglobulin heavy chain locus V H see IGH CH1 κ Fab VL immunoglobulin light chain the or λ light chain of immunoglobulin CL Hinge immunoglobulin M a pentomeric C 2 µ Fc H immunoglobulin with heavy chains, responsible for the primary immune C 3 H response (see Fig. 48) immunoperoxidase technique a technique for recognizing antibodies (b) V H which have bound to antigen, achieved CH1 VL by linking the antibody to peroxidase

CL (direct immunoperoxidase technique) or utilizing a peroxidase-conjugated anti- CH2 Secetory immunoglobulin which binds to the first component CH3 antibody (indirect immunoperoxidase J chain technique) immunophenotype the antigenic characteristics of a population of cells immunophenotyping the recognition of the antigenic profile of a population or populations of cells (see Fig. 28, p. 104) impedance a measurement of the flow of electrical current between two electrodes suspended in a conducting medium; an immunoglobulin gene rearrange- alteration of impedance can be a con- ment the bringing together of non- sequence of the passage of a cell or other contiguous DNA sequences from the V, D particle between the electrodes and J regions of the immunoglobulin heavy impedance counter an automated chain locus or similarly the kappa locus counter using impedance technology to or the lambda locus (see Fig. 46, p. 135) count and size cells HAE-I 01/13/2005 05:12PM Page 140

140 incidence

incidence the rate of occurrence of a dis- INK4b see CDKN2B and Table 5, p. 70 ease in a population, usually expressed as innate immunity naturally occurring the number of cases per 100 000 of popu- immunity that is not permanently changed lation per year by encounter with an antigen, dependent Indian a blood group system, the antigens on phagocytic cells, natural killer cells, being carried on CD44, the hyaluronate inflammatory mediators, acute phase receptor reactants and complement components ineffective not achieving the desired end ins a cytogenetic abbreviation indicating ineffective erythropoiesis failure to an insertion achieve adequate bone marrow output of insertion either (i) the insertion of part erythrocytes despite normal or increased of one chromosome into another chro- numbers of erythroid precursors in the mosome or into another part of the same bone marrow, indicative of increased chromosome, detectable by conventional intramedullary death of erythroblasts cytogenetic analysis and designated ‘ins’, ineffective haemopoiesis failure to or (ii) the insertion of a number of bases achieve adequate bone marrow output into a DNA molecule of erythrocytes, leucocytes and platelets in situ a method of studying a cell or a despite normal or increased numbers of tissue without disrupting it so that posi- haemopoietic precursors in the bone tive or negative results can be related to marrow, indicative of increased intra- individual cells medullary death of haemopoietic cells in situ hybridization a technique for infarct death of a tissue as a result of detecting specific DNA or RNA sequences interruption of its blood supply by hybridization with a complementary infectious mononucleosis glandular probe that is labelled, for example, with a fever; an acute illness with fever, pharyn- fluorochrome or a radioactive isotope gitis, lymphadenopathy and atypical lym- integrin one of a family of heterodimeric phocytes in the peripheral blood. Caused transmembrane cell adhesion molecules, by primary infection with the Epstein– composed of non-covalently linked α Barr virus and β subunits, that mediate cell–cell inflammation non-specific changes in and cell–matrix interactions tissues as a response to infection or tissue interdigitating dendritic cell a tissue damage cell (including Langerhans cells) that be- ING1 a gene, Inhibitor of Growth 1, gene comes activated on antigen exposure and map locus 13q34, encodes a widely ex- migrates to draining lymph nodes where pressed zinc finger nuclear protein which it presents antigen to helper T lymphocytes causes cell cycle arrest in G1; a candidate in the context of major histocompatibility tumour suppressor gene, mutations have complex class II molecules been found in squamous cell carcinomas interferon one of a family of cytokines of the head and neck produced by various body cells, e.g. INK4a see CDKN2A and ARF monocytes, fibroblasts and virus-infected INK4b see CDKN2B cells, that are part of non-specific immune initiation (i) the process by which RNA response to viruses and to cancer cells; transcription from a gene commences; (ii) they are categorized as type 1 (α and β) the process by which protein translation and as type 2 (γ); interferons are used in from mRNA commences (see Fig. 74, therapy, e.g. to treat chronic granulocytic p. 222) leukaemia and hairy cell leukaemia initiation codon the three nucleotide interferon-α one of two classes of codon (ATG) at the 5′ end of a gene cytokines synthesized by virus-infected which is essential to permit initiation of cells that conveys, to other cells, resist- transcription of a gene, i.e. initiation of ance against viral infection polypeptide synthesis interferon-β one of two classes of cyto- INK4a see CDKN2A and Table 5, p. 70 kines synthesized by virus-infected cells HAE-I 01/13/2005 05:12PM Page 141

interleukin-9 (IL9) 141

that conveys, to other cells, resistance tions in it are associated with congenital against viral infection immunodeficiency interferon-γ a cytokine synthesized by interleukin-3 (IL3) a haemopoietic type 1 (Th1) helper T cells and NK cells, colony-stimulating factor, encoded by encoded by a gene on chromosome 6; IL3, that is capable of supporting the γ interferon activates macrophage and proliferation of a broad range of haemo- neutrophil killing, stimulates NK cell poietic cell types and also has neu- function and enhances antigen-presenta- rotrophic activity tion by increasing expression of type II interleukin-4 (IL4) a lymphokine MHC molecules; it inhibits type 2 (Th2) secreted by type 2 (Th2) helper T cells helper T cells; a defect in γ-interferon or and activated B cells, encoded by IL4, its receptor can cause an inherited suscep- which activates macrophages and B tibility to mycobacterial infections cells, promotes IgE class switching and interferon regulatory factor (IRF) a has a role in mast cell sensitization, family of transcription factors defined by allergy and defence against nematodes; a characteristic DNA-binding domain it stimulates the production of eotaxin—a and the ability to bind to the interferon- chemokine involved in eosinophil recruit- stimulated response element; involved in ment; has an inhibitory effect on the cytokine signalling and the control of growth of many leukaemic cell lines in vitro proliferation interleukin-5 (IL5) a haemopoietic interleukin a cytokine secreted by one growth factor for B cells and eosinophils, type of leucocyte that has effects mainly secreted by type 2 (Th2) helper T cells, on other leucocytes encoded by IL5 interleukin-1 (IL1) a cytokine, also interleukin-6 (IL6) a cytokine with known as endogenous pyrogen, pro- potent antiviral activity, which is also duced mainly by monocytes, that able to elicit an acute phase response; activates T cells and macrophages and encoded by IL6; the aberrant production mediates the acute phase response; there of IL6 by neoplastic cells is a contribu- are 2 forms encoded by 2 separate genes tory factor to the growth B-cell neo- at 2q14 plasms, T-cell lymphomas and Kaposi’s interleukin-2 (IL2) an immunoregula- sarcoma; promoter polymorphisms in tory lymphokine, encoded by IL2, pro- the IL6 gene are associated with hyper- duced by activated type 1 (Th1) helper T triglyceridaemia and susceptibility to cells, which activates cytotoxic T cells, Kaposi’s sarcoma in HIV-infected indi- NK cells and macrophages viduals, but there is no association with interleukin-2 receptor the multi- multiple myeloma. subunit IL2 receptor that is composed of interleukin-7 (IL7) a lymphokine cap- various heterotrimeric and heterodimeric able of supporting the growth of pre-B combinations of three different subunits, cells in vitro, encoded by IL7 IL2Rα, also known as CD25 (encoded by interleukin-8 (IL8) a cytokine secreted IL2RA), IL2Rβ, also known as CD122, by several types of cell, including T cells (encoded by IL2RB) and IL2Rγ, also and macrophages, in response to inflam- known as CD132 (encoded by IL2RG); matory stimuli, encoded by IL8; it is the gamma chain is an indispensable chemotactic for neutrophils, basophils component of the receptor and is also a and T cells and promotes angiogenesis; component of other cytokine receptors involved in the pathogenesis of viral (see CD132); αβγ trimers constitute the bronchiolitis caused by the respiratory high affinity form of the receptor, βγ syncytial virus (RSV)—the level of IL8 dimers the intermediate affinity form and appears to be correlated with disease αγ dimers the low affinity form; the α severity chain is not functional in IL2 internaliza- interleukin-9 (IL9) a cytokine with both tion and signal transduction, but muta- myeloid and lymphoid stimulatory activ- HAE-I 01/13/2005 05:12PM Page 142

142 interleukin-10 (IL10)

ity, encoded by IL9; it promotes IgE class similarly to IL2, encoded by IL15; it switching; overproduced in Hodgkin’s appears to utilize the IL2 receptor disease interleukin-16 (IL16) a proinflammat- interleukin-10 (IL10) an anti- ory cytokine which signals via CD4, inflammatory cytokine secreted by type 2 inducing chemotactic and immunomodu- (Th2) helper T cells, which down regulatory responses in CD4+ T cells; lates the immune response, inhibiting encoded by IL16 type I (Th1) helper T cells and inhibits interleukin-17 (IL17) a proinflam- allergic reactions, encoded by IL10; matory cytokine expressed by activated interleukin-10 limits HIV-1 replication in memory T cells, encoded by IL17; induces vivo; mutations in the IL10 promoter expression of CD54 on B cells; archetypal have been associated with increased risk member of a new family of proinflamma- of HIV infection and once infected, rapid tory cytokines (IL17 B–F) progression to AIDS interleukin-18 (IL18) a cytokine secreted interleukin-11 (IL11) a widely expres- by macrophages, encoded by IL18, which sed cytokine of unknown physiological promotes interferon-γ secretion by T function, encoded by IL11; acts synergis- cells, suppresses IgE synthesis and aug- tically with several other cytokines to ments NK cell responses stimulate cells of a variety of haemo- interleukin 19 (IL19) a cytokine closely poietic lineages; secreted by bone marrow related to and genetically linked with stromal cells; stimulates the production IL10 and IL20; regulates B-cell function; of acute phase proteins encoded by IL19 interleukin-12 (IL12) a dimeric interleukin 20 (IL20) a cytokine closely cytokine, also known as natural killer cell related to and genetically linked with stimulatory factor, composed of an alpha IL10 and IL19; encoded by IL20; IL20 chain (p35 subunit encoded by IL12A) receptors are found in the skin and are and a beta chain (p40 subunit encoded upregulated in psoriasis by IL12B); secreted by dendritic cells, intermediate filaments filaments with macrophages and B cells; stimulates a diameter of 7–10 nm that form part of the production of interferon-γ by type 1 the cytoskeleton; they include keratin, helper T cells and NK cells; mutations desmin, vimentin, laminin, neurofilaments in IL12B or IL12R lead to inherited sus- and glial fibrillary acidic protein ceptibility to mycobacterial infections, intermediate grade lymphoma a including disseminated infection with lymphoma with a degree of malignancy BCG, and to susceptibility to Salmonella intermediate between low and high grade, enteritidis infection recognized by the Working Formulation; interleukin-13 (IL13) a cytokine includes mantle cell lymphoma which was secreted by activated type 2 (Th2) previously sometimes designated ‘lym- helper T cells, encoded by IL13, which phoma of intermediate differentiation’ stimulates the production of eotaxin, a interphase the stage when a cell is out of chemokine involved in eosinophil recruit- cycle (G0) (see Fig. 15, p. 72) ment; induces IgG4 and IgE synthesis interstitial pertaining to the interstitium by B cells; induces the pathophysiologic interstitium the potential space between features of asthma, independently of IgE cells and eosinophils; polymorphisms in the intervening sequence (IVS) see intron IL13 gene predispose to bronchial hyper- intracerebral within the brain responsiveness and asthma susceptibility intracranial within the skull interleukin-14 (IL14) a cytokine with intrasinusoidal within a sinusoid, e.g. B-cell stimulatory properties, gene map within a bone marrow sinusoid locus unknown intravascular within blood vessels interleukin-15 (IL15) a cytokine which intravenous within a vein (usually re- affects T-cell activation and proliferation ferring to a method of administering HAE-I 01/13/2005 05:12PM Page 143

IRTA1 143

blood or blood components, ﬂuids or iron-binding capacity the capacity of drugs) the serum to bind iron, dependent on the intrinsic contained within itself concentration of transferrin and other intrinsic factor a factor secreted by the iron-binding proteins in the serum parietal cells of the stomach that com- iron deﬁciency a lack of adequate iron bines with an extrinsic or dietary factor stores leading to some clinical or labora-

(vitamin B12 ) to permit the absorption of tory abnormality, e.g. anaemia or glossitis vitamin B12 in the small intestine iron deﬁciency anaemia anaemia intrinsic factor antibodies antibodies caused by a lack of adequate supplies directed at intrinsic factor, often present of iron in the serum or the gastric juice of indi- iron depletion absence of storage iron viduals with pernicious anaemia but without any associated haematolog- intrinsic pathway a coagulation path- ical or clinical abnormality way for which all the factors necessary iron-regulatory proteins proteins that are already present in the blood, only con- interact with iron-responsive elements of tact with a foreign surface being required genes; in the case of the ferritin genes and to initiate coagulation (see Fig. 17, p. 77) the δ-aminolaevulinate synthase gene, iron intron a sequence of DNA in a gene depletion leads to interaction and decrea- which is not represented in processed sed translation of the gene; in the case of messenger RNA or in the protein product the transferrin receptor gene, iron deple- (see Fig. 32, p. 111) tion leads to interaction and increased inv a cytogenetic abbreviation indicating translation of the gene an inversion iron-responsive element a family of inversion (inv) the inversion of a seg- cis-acting non-coding mRNA structures ment of a chromosome located in the untranslated region of in vitro carried out or occurring outside mRNA for ferritins, δ-aminolaevulinate a living body, literally ‘in glass’ synthase and transferrin receptor in vivo carried out or occurring in a iron stores iron stored in body macro- living creature, literally ‘in life’ phages in the form of ferritin and, par- ion an atom that has gained or lost one of ticularly, haemosiderin its electrons so that it is not electrically irradiation exposure to ionizing radiation balanced irregularly contracted cells erythro- IRF interferon regulatory factor cytes lacking central pallor but, in con- IRF1 a gene, Interferon Regulatory trast to spherocytes, being irregular in Factor 1, gene map locus 5q31.1, encodes shape an IRF transcription factor that upregu- IRTA1 a gene, Immunoglobulin lates several growth-suppressing genes; superfamily Receptor Translocation- hemizygously lost in some patients Associated gene 1, gene map locus 1q21, with 5q–; mutations leading to variant one of 5 related genes (IRTA1-5) clus- proteins with reduced DNA-binding tered at this locus; encodes an inhibitory capacity have been observed in gastric immunoglobulin superfamily receptor and non-small cell lung carcinoma homologous to the Ig Fc receptor, nor- IRF4 a gene, Interferon Regulatory Factor mally expressed in perifollicular B cells 4, also known as Multiple Myeloma but not in plasma cells; IRTA1 is trans- oncogene 1—MUM, gene map locus 6p25, located to the IGH locus in t(1;14)(q21;q32) encodes an IRF transcription factor associated with less than 5% of cases expressed only in lymphocytes; dysregu- of multiple myeloma, the fusion gene lated by t(6;14)(p25;q32) in about 20% of encoding a protein containing the signal patients with multiple myeloma. peptide and ﬁrst two amino acids of iron Fe, a metal which is an essential con- IRTA1 linked to the transmembrane and stituent of haemoglobin and the muscle intracellular domains of the surface IgA protein, myoglobin receptor HAE-I 01/13/2005 05:12PM Page 144

144 IRTA2

IRTA2 a gene, Immunoglobulin superfamily isotype immunoglobulin molecules char- Receptor Translocation-Associated gene acterized by a specific type of heavy chain, 2, gene map locus 1q21, encodes an e.g. immunoglobulin M rather than inhibitory immunoglobulin superfamily immunoglobulin A receptor homologous to the Ig Fc recep- isotype switching change from secret- tor, normally expressed in germinal cen- ing immunoglobulin M to secreting another tre centrocytes and a broad spectrum of class of immunoglobulin, e.g. IgG or IgA perifollicular cells, which may include ITGA2 the gene at 5q23-q31 encoding the α α β immunoblasts and memory cells but not integrin 2 chain; integrin 2 1 (very late centroblasts; dysregulated and overex- antigen-2, VLA-2) is platelet glycopro- pressed in Burkitt’s lymphoma with 1q21 tein Ia/IIa (CD49b/CD29) abnormalities, being the only member of ITGA2B the gene at 17q21.32 encod- α the IRTA cluster to be expressed in this ing the integrin IIb chain (CD41a), a disorder—the mechanism for this is unclear component of platelet glycoprotein IIb/ ISBT International Society for Blood IIIa, mutation of which can lead to Transfusion Glanzmann’s thrombasthenia iso (or i) a cytogenetic abbreviation ITGB2 the gene encoding CD18, the inte- indicating an isochromosome grin β2 chain, mutation of which can isochromosome (i or iso) a chromo- cause leucocyte adhesion deficiency some formed by duplication of either the ITGB3 the gene at 17q21.32 encoding β short arm or the long arm of a chromosome the integrin 3 chain (CD61), a com- isoenzyme a structurally different form ponent of platelet glycoprotein IIb/IIIa α β of an enzyme present in different tissues ( IIb/ 3) and the vitronectin receptor α β of a single individual ( v / 3); mutation of the gene can lead to isoniazid a drug used to treat tuberculosis Glanzmann’s thrombasthenia which can cause sideroblastic erythropoiesis ITP idiopathic thrombocytopenic pur- isotonic having an osmolarity that is the pura (now usually referred to as ‘autoim- same as that of normal body fluids mune thrombocytopenic purpura’) HAE-J 01/13/2005 05:12PM Page 145

JAK janus kinase Jordan’s anomaly an inherited abnor- JAK2 a gene, Janus kinase 2, gene map mality in which leucocytes of all types are locus 9p24, encodes a janus kinase; JAK2 vacuolated contributes to the ETV6-JAK2 fusion jumping translocation translocation of gene in rare cases of acute lympho- part of a chromosome to multiple other blastic leukaemia and atypical chronic partner chromosomes myeloid leukaemia, associated with JUN a transcription factor of the leucine either t(9;12)(p24;p13) or with a com- zipper family plex rearrangement with the same JUN a gene, gene map locus 1p32, that breakpoints encodes a leucine zipper DNA-binding JAK3 a gene encoding a janus kinase, protein which is the cellular homologue mutation of which can cause severe of the transforming gene of avian sar- combined immune deﬁciency coma virus 17; JUN is a major compon- Janus kinase (JAK) a family of non- ent of the activator protein-1 (AP-1) receptor tyrosine kinases that are involved transcription factor complex in intracellular signalling via a variety of juvenile chronic myeloid leukaemia cytokines; characterized by having two a type of chronic myeloid leukaemia phosphotransferase domains which occurs in infants, characterized by jejunum the proximal small intestine, hepatosplenomegaly, lymphadenopathy, between the duodenum and the ileum, rash, anaemia, monocytosis and eleva- the site of maximal folic acid absorption tion of haemoglobin F concentration, Jk a and Jk b co-dominant alleles at the now usually designated juvenile myelo- HUT11 locus, encoding antigens of the monocytic leukaemia Kidd blood group system (see also Kidd juvenile myelomonocytic leukaemia and HUT11) an alternative designation of juvenile chronic Jka, Jkb and Jk3 antigens of the Kidd myeloid leukaemia, the term recommended blood group system (see also Kidd and in the WHO classiﬁcation (see Fig. 55, HUT11) p. 168)

145 HAE-K 01/13/2005 05:13PM Page 146

κ kappa, one of the two types of light or individual, conforming to certain chain found in about 60% of immuno- conventions as to how abnormalities are globulin molecules described, e.g. a male with Klinefelter’s κ the kappa immunoglobulin light chain syndrome would be described as hav- gene, gene map locus 2p12; transloca- ing the karyotype 47,cXXY whereas tions involving this locus can lead to a female with chronic granulocytic dysregulation of other genes, e.g. MYC leukaemia would be expected to have a or BCL2 leukaemic clone with the karyotype Kaposi’s sarcoma a sarcoma of end- 46,XY,t(9;22)(q34;q11) othelial cells which in common in AIDS; karyotypic pertaining to a karyotype very rarely it inﬁltrates the bone marrow Kawasaki’s syndrome an acute febrile karyogram an ordered array of chromo- multisystem disease of children with cer- somes of a cell, usually a photograph with vical lymphadenopathy, changes in skin the pairs of chromosomes arranged in and mucous membranes and coronary decreasing size (Fig. 49) arteritis karyotype an abbreviated written de- kb a kilobase scription of the karyogram of a cell, clone kD a kilodalton

Figure 49 A karyogram. A karyogram of a patient with chronic granulocytic leukaemia showing cytogenetic evolution. The primary abnormality present was t(9;22)(q34;q11). A secondary abnormality has occurred, t(3;21)(q26;q22).

146 HAE-K 01/13/2005 05:13PM Page 147

knockout mouse 147

Figure 50 A keratocyte. kilodalton (kD) 1000 Daltons A keratocyte showing two ‘horns’. Kimura’s disease a chronic inflammatory disease of unknown aetiology, causing lymphadenopathy with reactive follicular hyperplasia and infiltration by eosinophils kinase an enzyme that transfers a phosphate group KIP1 see CDKN1B KIP2 see CDKN1C KIT a gene, gene map locus 4q11-34, encoding stem cell factor receptor, a receptor tyrosine kinase; KIT protein is recognized by CD117 monoclonal antibodies; KIT is expressed on haemopoietic progenitors, megakaryocytes, mast cells and KEL a locus at 7q33 where there are three a subset of NK cells; it is often overex- closely linked sets of alleles encoding pressed in acute myeloid leukaemia and is antigens of the Kell blood group system usually mutated, leading to constitutive (CD238); the most important of the 25 activation of KIT, in systemic mastocyto- known antigens and the genes encoding sis; mutated in gastrointestinal stromal them are: tumours, some germ cell tumours and •K (KEL1) and k (KEL2) some sino-nasal NK/T cell lymphoma. •Kpa (KEL3), Kpb (KEL4) and Kpc Kleihauer test a cytochemical stain for (KEL21) demonstrating erythrocytes, including •Jsa (KEL6) and Jsb (KEL7) fetal erythrocytes, with a high concentra- Kell a red cell-specific blood group sys- tion of haemoglobin F tem, see also KEL knockin mouse an experimental animal keratocyte a cell with one or two pairs from which, by means of manipulating of spicules, symmetrically arranged and selecting embryonal stem cells, a (Fig. 50) specific gene has been ‘knocked in’ so that kernicterus damage to the basal ganglia its function can be studied of the brain by a high concentration of knockout mouse an experimental bilirubin, e.g. in haemolytic disease of the animal from which, by means of mani- newborn pulating and selecting embryonal stem Ki-1 a monoclonal antibody that recog- cells, a specific gene has been ‘knocked nizes the CD30 cluster out’ and replaced by a disabled gene Ki-1+ lymphoma an earlier designation of anaplastic large cell lymphoma Ki-67 a monoclonal antibody that iden- tifies proliferating cells Figure 51 Koilonychia. KIAA0128 see Septin 2 Koilonychia in a patient with iron deficiency. Kidd a blood group antigen system including the Jka and Jkb antigens (see also HUT11) Kiel classification a lymphoma classification which was largely superseded by the REAL classification (see Revised European–American Lymphoma classification) and then by the WHO classification killer cell a lymphocyte which can kill another cell kilobase (kb) 1000 base pairs of DNA HAE-K 01/13/2005 05:13PM Page 148

148 Knops

Knops a blood group system, the anti- neutropenia; a minority of case result gens being carried on CD35, a comple- from heterozygosity for a mutation in the ment regulatory protein, the C3b/C4b gene encoding the receptor for granulo- receptor cyte colony-stimulating factor (G-CSFR) koilonychia ﬂat or spoon-shaped nails kwashiorkor a form of protein-calorie as a feature of iron deﬁciency (Fig. 51) malnutrition Kostmann’s syndrome an inherited abnormality causing severe congenital HAE-L 01/13/2005 05:13PM Page 149

λ the Greek letter lambda, one of the characterized by the presence of specific types of light chain found in about 40% of cytoplasmic granules designated Birbeck immunoglobulin molecules granules λ the lambda immunoglobulin light chain Langerhans cell histiocytosis a group gene, gene map locus 22q11; transloca- of neoplastic conditions of Langerhans tions involving this locus can lead to cells, previously designated histiocytosis dysregulation of other genes e.g. MYC X, further categorized as Letterer–Siwe or BCL2 disease, Hand–Schüller–Christian disease L1, L2, L3 categories in the FAB class- and eosinophilic granuloma ification of acute lymphoblastic leukaemia Langerhans cell leukaemia an acute labelling index the proportion of cells leukaemia of Langerhans cell lineage, in which DNA synthesis is occurring, occurring de novo or as the terminal phase determined, for example, by incorpora- of Langerhans cell histiocytosis tion of tritiated thymidine or bromo- Langhans type giant cell a multi- deoxyuridine nucleated giant cell of monocyte lineage lactate dehydrogenase (LDH) an characterized by peripherally placed nuclei enzyme found in many body cells that LAP leucocyte alkaline phosphatase catalyses the oxidation of L-lactate to laparoscopy inspection of the abdom- pyruvate, elevated in haemolytic anaemia inal cavity by means of a laparoscope and in ineffective haemopoiesis inserted through a small incision lactic acid the end product of anaerobic laparotomy surgical exploration of the metabolism abdomen for diagnostic or therapeutic lactoferrin an iron-binding protein purposes found in neutrophils (and also milk and LARG a gene, Leukaemia-Associated other body fluids) that retards bacterial Rho Guanine nucleotide exchange factor, proliferation also known as Rho Guanine nucleotide lactoferrin deficiency see neutrophil Exchange Factor 12, RHGEF12; gene specific granule deficiency map locus 11q23, encodes a guanine LAF4 a gene, Lymphoid nuclear protein nucleotide exchange factor (GEF) with related to AF4, gene map locus 2q11.2- homology to BCR; contributed to a q12, encodes a lymphoid-restricted tran- MLL-LARG fusion gene in a patient with scriptional activator that is a homologue acute myeloid leukaemia and a complex of AF4 and AF5q31; contributed to a karyotype fusion gene in a case of acute lymphoblas- large cell anaplastic lymphoma a tic leukaemia large cell lymphoma of T lineage with LAK cell lymphokine-activated killer cell cells showing strong CD30 positivity and lamellar bone bone with an orderly sometimes aberrant positivity for epithe- structure of concentric layers surround- lial membrane antigen ing a central Haversian canal large cell lymphoma a lymphoma of Langerhans cell a cell of monocyte large lymphoid cells of T, B or NK lineage, normally found in the skin and lineage

149 HAE-L 01/13/2005 05:13PM Page 150

150 large granular lymphocyte

large granular lymphocyte a large encoding transcriptional coactivators, lymphocyte with plentiful cytoplasm and p52 and p75, which differ at their carboxy prominent azurophilic granules terminal ends; contributed to a LEDGF- large granular lymphocyte leukaemia NUP98 fusion gene in a patient with de a leukaemia of large granular lympho- novo acute myeloid leukaemia; the fusion cytes of either T or NK lineage protein lacks the transactivating domain large unstained cell (LUC) a term used of LEDGF to describe large, peroxidase-negative left shift an increased proportion of cells detected by Bayer automated immature cells of neutrophil lineage in instruments either the peripheral blood or the bone larynx the part of the throat that con- marrow tains the vocal cords Leishman–Donovan bodies the rest- LAZ an alternative designation of BCL6 ing stage of Leishmania donovani observed lazy leucocyte syndrome a syndrome in tissues including the bone marrow of recurrent infections associated with leishmaniasis infection by the parasite defective response of neutrophils to Leishmania donovani or related species chemotactic stimuli Lennert’s lymphoma an alternative LCAT lecithin-cholesterol acyl transferase designation of lymphoepithelioid lym- LCP1 a gene, Lymphocyte Cytosolic phoma of the Kiel classification, included Protein 1, gene map locus 13q14.1, an in the ‘peripheral T-cell lymphoma, IL2-responsive gene that encodes an unspecified’ category of the REAL class- actin-binding protein; contributes to the ification and the WHO classification LCP1-BCL6 fusion gene in B-lineage lepirudin a recombinant form of hirudin, non-Hodgkin’s lymphoma associated a thrombin inhibitor with t(3;13)(q27;q14); as a result of the Lermitte’s syndrome tingling feelings translocation, the 5′ regulatory regions spreading down the body when the of the two genes are exchanged head is bent forward, which may occur

Leach phenotype an inherited anomaly in vitamin B12 deficiency and following of the erythrocyte membrane associated irradiation for Hodgkin’s disease with loss of the Gerbich antigens and Letterer–Siwe disease a highly aggres- elliptocytosis sive form of Langerhans cell histiocytosis LE cell a neutrophil with a round homo- occurring in infants geneous inclusion representing altered leucapheresis removal of white cells from nuclear material, characteristic of sys- the peripheral blood, usually either to temic lupus erythematosus, and demon- relieve hyperviscosity or to obtain cells for strated by incubating neutrophils with peripheral blood stem cell transplantation the patient’s serum leucine rich repeat (LRR) a hydropho- lecithin-cholesterol acyl transferase bic protein motif believed to participate deficiency (LCAT deficiency) an in protein-protein interactions inherited metabolic disorder associated leucine zipper a protein motif char- with increased target cell formation acterized by a leucine residue occurring lectin any protein other than an every 7th base; required for homodimer- immunoglobulin that binds to a specific ization and heterodimerization carbohydrate group, may be of plant, leucocyte a white blood cell, a term microbial or animal origin; may be used which includes all the mature peripheral for identification of antigens (e.g. blood blood cells of granulocyte, monocyte group antigens) or to stimulate cell or lymphocyte lineage, i.e. neutrophils, growth and proliferation eosinophils, basophils, lymphocytes and Leder stain a histochemical stain to monocytes demonstrate chloroacetate esterase activity leucocyte adhesion deficiency a LEDGF a gene, Lens Epithelium-Derived genetically heterogeneous group of Growth Factor, gene map locus 9p22, conditions in which there is defective HAE-L 01/13/2005 05:13PM Page 151

loiasis 151

adhesion of neutrophils to endothelium, light chain the shorter polypeptide leading to neutrophilia, a lack of extra- chain of a heterodimer; if not otherwise vascular neutrophils and susceptibility specified, the term applies to the light to infection: type 1 results from muta- chain of the immunoglobulin molecule, tion in the ITGB2 (integrin β2) gene, the each molecule having two heavy chains gene encoding the β chain of the leuco- and two light chains; light chains may be cyte integrins, which results in CD18 kappa or lambda but in a given molecule deficiency; type 2 results from a defect are one or the other in carbohydrate fucosylation so that light chain-associated amyloidosis endothelial sialyl-Lewisx is not expressed amyloidosis occurring as a complication and endothelium cannot bind E and P of a plasma cell neoplasm, either overt selectins (see CD62E and CD62P); a or occult, previously often designated single case has also been reported in ‘primary amyloidosis’ when the plasma which there was deficiency in RAC2, the cell neoplasm was occult predominant GTPase in neutrophils light chain deposition disease dis- leucocyte alkaline phosphatase (LAP) ease resulting from deposition of a mono- the alkaline phosphatase isoenzyme in clonal light chain in tissues, particularly neutrophils; it should be noted that the in the kidneys term ‘neutrophil alkaline phosphatase’ LIM domain a zinc-binding protein and the abbreviation ‘NAP’ are to be motif which provides an interface for preferred protein interactions leucocytosis an increased number of linkage the presence of two or more leucocytes in the peripheral blood genes sufficiently close to each other on a leucoerythroblastic anaemia ana- chromosome that they do not segregate emia with both erythroblasts and granu- independently locyte precursors in the peripheral linkage disequilibrium the association blood of particular genes or other DNA leucopenia a reduced white cell count sequences more frequently than would leukaemia a myeloid or lymphoid be expected by chance neoplasm, characterized by circulating lithium a drug used for treating depres- neoplastic cells but also encompassing sion that elevates the neutrophil count similar cases in which there are neoplastic LMAN1 a gene at 18q21.3-q22, encoding cells in the bone marrow but not in the an intracellular mannose-specific protein peripheral blood that is involved in transport of early pro- leukaemic reticuloendotheliosis an cessed glycoproteins from endoplasmic early designation of hairy cell leukaemia, reticulum to the Golgi apparatus; muta- not in current use tion can lead to combined factor V and leukaemogenesis the mechanism of factor VIII deficiency development of leukaemia locus (plural loci) the specific site on a leukaemoid reaction a reactive condi- chromosome where a gene and its alleles tion which simulates or closely resembles are located leukaemia LOD score a statistical test of linkage; Lewis blood group system a blood the higher the LOD score the less the pos- group system in which plasma glycosph- sibility that the association could occur ingolipids, resulting from the expression by chance of alleles at the FUT1, FUT2, FUT3 and log normal distribution having a ABO loci, are adsorbed onto red cells Gaussian or bell-shaped distribution (see Fig. 30, p. 108) when the logarithm of the data is plotted ligand a molecule that binds specifically as a histogram (see Fig. 45, p. 128) to another molecule, e.g. stem cell factor LOH loss of heterozygosity is the ligand of c-KIT and thrombopoietin loiasis the disease resulting from infec- is the ligand of MPL tion by the filarial parasite, Loa loa HAE-L 01/13/2005 05:13PM Page 152

152 lomustine (CCNU)

lomustine (CCNU) an anti-cancer drug Figure 52 A lymphangiogram. of the nitrosourea family A lymphangiogram, showing images of lymph nodes long term culture initiating cells which have trapped an oily radio-opaque dye that (LTCIC) cells that are able to give rise to was injected into lymphatic vessels in the feet; the normal lymph nodes are small and have a fairly long term cultures in vitro homogeneous texture whereas abnormal lymph loss of heterozygosity (LOH) loss of nodes, identifiable below the left kidney, are large one allele at a specific locus and heterogeneous in texture; an intravenous low hyperdiploidy having 47–50 chro- pyelogram has also been performed so that the renal mosomes in a cell or clone pelvises and the ureters are outlined, showing that low molecular weight heparin hep- the left ureter is deviated around a group of abnormal lymph nodes; the patient had Hodgkin’s arin that has been depolymerized so that disease. the molecular weight is in the range of 4000 to 5000 daltons, e.g. enoxaparin, dalteparin, tinzaparin, ardeparin LPP a gene, LIM domain containing Preferred translocation Partner in lipoma, also known as Lipoma Preferred Partner, gene map locus 3q28, encodes a putative cell adhesion molecule that contains a LIM domain; contributed to MLL-LPP and LPP-MLL fusion genes in a patient with secondary M5 acute myeloid leukaemia with t(3;11)(q28;q23) LTCIC long term culture initiating cells LU the gene at 19q13.2 encoding the Lua and Lub antigens of the Lutheran blood group system LUC large unstained cell lupus anticoagulant an antibody that is an anticoagulant in vitro but is pro- thrombotic in vivo, occurs in systemic lupus erythematosus and in the primary antiphospholipid syndrome; paraproteins may also be lupus anticoagulants by lymphatics and ultimately drains into Lutheran a blood group system, Lutheran the blood stream through the thoracic duct antigens (CD239) being encoded by the lymphadenopathy enlargement of the genes at the LU locus lymph nodes LW a locus at 19p13.3 encoding LW lymphangiogram a radiological proce- blood group antigens dure for demonstrating lymph nodes by LW a blood group antigen system (CD242) means of radio-opaque dye introduced encoded by genes at the LW locus into lymphatics on the dorsum of the feet LYL1 a gene, Lymphoid Leukaemia gene, (Fig. 52) gene map locus 19p13, encodes a basic lymphatic (i) relating to lymphocytes and helix–loop–helix (bHLH) transcription lymph nodes (ii) an endothelium-lined factor closely related to TAL1, which is vessel which transports lymph expressed in all haemopoietic cells except lymph follicle an organized nodule of for T cells, dysregulated by proximity to mature B lymphocytes—smaller cells, the TCRB gene at 7q35 in T-lineage acute designated follicle centre cells or centro- lymphoblastic leukaemia associated with cytes, and larger cells, designated centrob- t(7;19)(q35;p13) lasts, in a lymph node or other tissue lymph a clear or opalescent fluid con- lymph gland a non-scientific term for taining lymphocytes, which is transported lymph node HAE-L 01/13/2005 05:13PM Page 153

lymphoma 153

Table 11 WHO classiﬁcation of T-cell and NK-cell neoplasms.

Precursor T-cell neoplasms Precursor T lymphoblastic leukaemia/lymphoblastic lymphoma Mature T-cell and NK-cell neoplasms Leukaemic/disseminated T-cell prolymphocytic leukaemia T-cell large granular lymphocyte leukaemia Aggressive NK-cell leukaemia Adult T-cell leukaemia/lymphoma Cutaneous Mycosis fungoides Sezary syndrome Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Other extra-nodal Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Nodal Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, unspeciﬁed Anaplastic large cell lymphoma Neoplasm of uncertain lineage and stage of differentiation Blastic NK-cell lymphoma

lymph node an organized tissue com- with specific histological features includ- posed mainly of T and B lymphocytes ing the presence of epithelioid cells, being with some stromal cells and dendritic cells recognized as a distinct entity in the Kiel lymphoblast an immature cell of lym- classification and included in the ‘periph- phoid lineage, having a high nucleocyto- eral T-cell lymphoma, unspecified’ cat- plasmic ratio, non-condensed chromatin egory of the REAL classification and the and nucleoli (see Fig. 12, p. 29) WHO classification lymphoblastic lymphoma a lym- lymphogranulomatosis a lymphopro- phoma composed of lymphoblasts, occur- liferative disorder, previously thought ring in a tissue other than the bone marrow to be reactive but probably a low grade lymphocyte a mature cell of lymphoid T-cell neoplasm lineage lymphoid pertaining to lymphocytes or lymphocytic pertaining to lymphocytes lymph nodes or to lymphoid cells lymphokine any type of molecule, lymphocytopenia a reduced lympho- other than an immunoglobulin mo- cyte count lecule, secreted by a lymphocyte and lymphocytosis an increased number of influencing the behaviour of other cells lymphocytes in the peripheral blood or tissues lymphocytotoxin also known as lym- lymphoma a neoplasm of lymphocytes photoxin and tumour necrosis factor β, (T, B or natural killer cells); in contrast to a cytokine secreted by B cells and type 1 lymphoid leukaemias, lymphomas involve helper T cells, which promotes inflamma- predominantly tissues other than the bone tion, encoded by a gene at 6p21 marrow, rather than the bone marrow lymphoepithelioid lymphoma Len- and blood; in the WHO classification, B- nert’s lymphoma, a T-cell lymphoma lineage and T-lineage lymphomas are HAE-L 01/13/2005 05:13PM Page 154

154 lymphoma of intermediate differentiation

designated as shown in Tables 10 (p. 137) transcriptionally active. The inactive X and 11 chromosome is responsible for the lymphoma of intermediate differen- neutrophil drumstick and in other cells tiation an earlier designation of mantle may be detected as a Barr body, a con- cell lymphoma densation of chromatin below the nuclear lymphopenia see lymphocytopenia membrane lymphoplasmacytoid lymphoma a lyonization the process by which one of lymphoma in which some of the neoplas- the two X chromosomes in each normal tic cells show plasma cell differentiation female cell becomes genetically inactive; lymphoproliferative disorder a this process occurs during early embry- generic term including all lymphomas and onic life and is maintained in the progeny also some disorders of undefined nature of that cell; it provides the basis of analy- in which there is abnormal lymphoid pro- sis of X-linked polymorphisms for pre- liferation of uncertain nature sumptive establishment of monoclonality lymphoproliferative T-cell deficiency lysis (i) destruction of a cell as a con- with autoimmunity syndrome an sequence of development of a hole in the immune deficiency syndrome resulting plasma membrane, e.g. destruction of a from mutation of the IL2 receptor gene at red cell following antibody binding and 10p14-15 with resultant CD25 deficiency complement fixation (ii) dissolution of a lymphosarcoma an outmoded term for thrombus non-Hodgkin’s lymphoma lysosome a cellular organelle into which Lyon hypothesis the hypothesis that hydrolytic enzymes are secreted, respons- one of the two X chromosomes in the ible for the degradation of foreign mater- cells of a normal female becomes inactive, ial and cellular debris this process occurring randomly so that, lysozyme an enzyme secreted by mono- on average, each X chromosome is cytes and, to a lesser extent, neutrophils inactive in 50% of cells; it is hypothesized lytic lesion an osteolytic lesion, gener- that the genetic inactivation of one chro- ally detected radiologically which, if there mosome permits X chromosomal dosage is no associated osteosclerosis, is suggest- compensation—no matter how many X ive of multiple myeloma chromosomes a cell has only one remains HAE-M 01/13/2005 05:13PM Page 155

µ the Greek letter, mu (i) the heavy chain macro-ovalocyte an oval macrocyte of immunoglobulin M (ii) the symbol for macrophage the end cell of the mono- a micron (iii) the symbol for one millionth cyte lineage, found mainly in tissues and, part of a unit, as in µg or µl being phagocytic, important in protection M the designation of the phase of the cell against infection; neoplasms of macro- cycle when mitosis occurs (see cell cycle) phage and related lineages are designated M0, M1, M2, M3, M4, M5, M6, M7 in the WHO classification as shown in categories in the FAB classification of Table 6, p. 127 acute myeloid leukaemia (see Table 3, p. 7) macrophage colony-stimulating fac- MAC the combined application of Mor- tor (M-CSF) a haemopoietic growth phology, Antibody and Chromosome factor, encoded by a gene at 1p13-21 techniques to the study of individual cells macropolycyte a very large neutrophil, McLeod phenotype a syndrome of probably usually tetraploid acanthocytosis, mild haemolytic anaemia, macrothrombocyte a large platelet myopathy and cardiomyopathy resulting macule a skin lesion which is not raised from deficiency of Kx protein and conse- MAD a gene, Max Dimerization protein, quent weak expression or lack of expres- gene map locus 2p13, archetypal mem- sion of Kell antigens ber of a small family of transcriptional macrocyte a large erythrocyte repressor proteins, which compete with macrocytic anaemia an anaemia char- MYC proteins for binding to MAX acterized by macrocytosis, e.g. in mega- MAF a gene, avian Musculoaponeuro- loblastic anaemia or the myelodysplastic tic Fibrosarcoma gene homologue, gene syndromes map locus 16q23, encodes a basic leucine macrocytosis having large erythrocytes zipper transcription factor; archetypal macroglobulinaemia an increased member of a family of such genes; MAF plasma concentration of macroglobulins, is dysregulated when brought into pro- specifically IgM ximity to the IGH locus in 30–35% of macroglossia a large tongue, may be a patients with multiple myeloma and feature of amyloidosis t(14;16)(q32;q23) macronormoblast an erythroblast MAFB a gene, avian Musculoaponeurotic which is larger than normal erythroblasts Fibrosarcoma oncogene homologue B, at the equivalent stage of development gene map locus 20q11, encodes a MAF but which does not show the nucleo- family basic region/leucine zipper tran- cytoplasmic asynchrony which is charac- scription factor; MAFB is translocated teristic of a megaloblast and overexpressed when t(14;20)(q32;q11) macronormoblastic maturation ery- brings it into proximity to the IGH locus throid maturation characterized by in some cases of multiple myeloma haemopoietic cells which are larger than magnetic resonance imaging (MRI) or normal but lack the nucleocytoplasmic nuclear magnetic resonance imag- asynchrony which is characteristic of ing (NMR) an imaging technique using megaloblastic haemopoiesis the inherent magnetic properties of body

155 HAE-M 01/13/2005 05:13PM Page 156

156 MAHA

Figure 53 A magnetic resonance imaging a Golgi-associated membrane protein; (MRI) scan. MAL is over-expressed in primary medi- A T2 weighted paracoronal magnetic resonance astinal (thymic) B-cell lymphoma and imaging (MRI) scan of the left shoulder; the humerus contributes to the OTT-MAL fusion gene has an irregular articular outline and high and low in infant M7 acute myeloid leukaemia signal bands in the subchondral region, typical of avascular necrosis; such lesions may be seen in associated with t(1;22)(p13;q13) patients with sickle cell disease. malabsorption failure to absorb nutrients normally; haematological effects

include deficiency of iron and vitamin B12 and folic acid and deficiency of vitamin K leading to coagulation defects malaria a disease resulting from infection by protozoan parasites of the Plas- modium genus malignant very injurious; in relation to neoplasms, aggressive and characterized by local invasion, distant spread (metastasis) and cytological differences from the equivalent normal tissues malignant histiocytosis a rare neoplasm of monocyte/macrophage lineage involving predominantly tissues other than the bone marrow; many patients reported to have had this condition have actually tissues containing free protons; para- had a reactive haemophagocytic syndrome magnetic molecules have their alignment malignant mastocytosis an aggressive changed by a combination of a strong widespread mast cell neoplasm, more magnetic field and radio frequency or less equivalent to aggressive systemic waves; as they regain their original posi- mastocytosis of the WHO classification tion radio frequency waves are emitted (see Table 12) which are then reconstructed into images malignant melanoma malignant (Fig. 53) tumour of cells analogous to melanocytes MAHA microangiopathic haemolytic but not necessarily pigment-producing anaemia malignant tertian malaria malaria MAIPA monoclonal antibody-specific caused by Plasmodium falciparum immobilization of platelet antigens MALT mucosa-associated lymphoid tissue major histocompatibility complex MALT-lymphoma or MALT-type (MHC) a group of polymorphic pro- lymphoma a lymphoma of cells ana- teins on the surface of cells, encoded by logous to normal mucosa-associated the HLA family of genes, which present lymphocytes modified antigen (as a short peptide in MALT a gene, Mucosa-Associated a surface groove) to T lymphocytes; Lymphoid Tissue lymphoma transloca- molecules are divided into class I and tion gene 1, also known as MLT; gene class II; class I molecules (HLA-A, HLA- map locus 18q21; encodes a cell surface B and HLA-C) are concerned with recog- adhesion molecule related to CD22, that nition of antigens expressed on altered is expressed strongly in blood, bone body cells and class II molecules (HLA- marrow, thymus and lymph node; con- DP, HLA-DQ and HLA-DR) with the tributes to the AP12-MLT fusion gene recognition of foreign antigens in MALT lymphoma associated with MAL a gene, T Lymphocyte Maturation- t(11;18)(q21;q21); in the presence of the Associated protein, also known as API2-MLT fusion protein there is MKL1, gene map locus 22q13, encodes sequestration of BCL10 in the nucleus HAE-M 01/13/2005 05:13PM Page 157

Maurer’s clefts 157

Table 12 The WHO classiﬁcation of mast cell disease (mastocytosis).

Cutaneous mastocytosis Indolent systemic mastocytosis Systemic mastocytosis with associated clinical, haematological an non-mast-cell lineage disease Aggressive systemic mastocytosis Mast cell leukaemia Extracutaneous mastocytoma

mannose-binding lectin an acute marker chromosome (mar) an abnor- phase reactant, synthesized by hepato- mal chromosome that cannot be charac- cytes, that binds to bacteria, yeasts and terized by routine cytogenetic techniques some viruses and parasites, thereby acti- mast cell a tissue cell of myeloid lineage vating mannose-associated proteases 1 which is involved in immune responses and 2, which initiate the lectin pathway of and in inflammation complement activation (see complement mast cell disease a WHO classification system and Fig. 20, p. 81) term for mast cell neoplasms, further mannose-binding lectin deficiency categorized as shown in Table 12 an inherited condition in which mutation mast cell leukaemia an acute in the MBL gene leads to reduced plasma leukaemia of mast cell lineage concentration of mannose-binding lectin, mastocytosis an increase in mast cells, inability to activate the mannose-binding an alternative generic term encompassing lectin complement pathway and recur- all mast cell neoplasms used in the WHO rent pyogenic infections classification being synonymous, in this mantle cell lymphoma a lymphoma of context, with ‘mast cell disease’ (see mature B cells analogous to lymphocytes Table 12) in the mantle zone of a lymph node matched unrelated donor (MUD) a mantle zone the circle of more darkly bone marrow or haemopoietic stem cell staining small lymphocytes that sur- donor who is unrelated to the recipient rounds the paler germinal centre but has been matched for histocompat- mar a cytogenetic abbreviation indicat- ibility antigens (note: the term ‘volunteer ing a marker chromosome unrelated donor (VUD)’ is now preferred) marasmus a form of protein-calorie matrix metalloproteinases enzymes, malnutrition with zinc at the active centre, that can marble bone disease see osteopetrosis cleave proteins of the extracellular march haemoglobinuria haemolytic matrix; they can be divided into four anaemia caused by mechanical trauma, main groups—collagenases, gelatinases, e.g. from long marches on hard earth stromeolysins and membrane-type marginal zone the zone between the metalloproteinases red and white pulp of the spleen including maturation development of the features the band of lymphocytes that surrounds characterizing later cells of the same lineage the lymphoid follicles of the white maturation arrest lack of maturing pulp; the marginal zone lymphocytes cells beyond a certain stage, e.g. arrest of are larger and paler than mantle zone granulopoiesis at the promyelocyte stage; lymphocytes usually indicates cell death at an inappro- marginal zone lymphoma a lym- priate stage during maturation but an phoma of mature B lymphocytes analo- apparent maturation arrest can also result gous to those in the marginal zone of from immune destruction of maturing cells lymphoid follicles; includes MALT-type Maurer’s clefts linear inclusions in lymphoma, splenic marginal zone lym- erythrocytes in Plasmodium falciparum phoma and monocytoid B-cell lymphoma malaria HAE-M 01/13/2005 05:13PM Page 158

158 MAX

MAX a gene, MYC-Associated factor X, tion of haemoglobin in an individual’s gene map locus 14q23, encodes a erythrocytes helix–loop–helix leucine zipper protein mean cell volume (MCV) the average which specifically heterodimerizes with size of an individual’s erythrocytes MYC transcriptional activators and median the value that divides a popula- permits their binding to their cognate tion into two numerically equal halves DNA binding sites (E-Boxes); also het- median disease-free survival the erodimerizes with MAD family proteins time when half of a studied population (which encode transcriptional repressors) is still alive and free of relapse and allows them to bind E-boxes, thereby median event-free survival the time antagonizing the effects of MYC proteins when half of a studied population has MAX a protein that forms heterodimers neither died nor suffered relapse nor with MYC protein changed to alternative treatment May–Grünwald–Giemsa (MGG) a median overall survival the time when Romanowsky type stain used to stain half of a studied population have died blood and bone marrow films and half are still alive, synonymous with May Hegglin anomaly an inherited median survival anomaly with giant platelets and neu- median survival the time when half of trophil inclusions resulting from a muta- a studied population have died and half tion in the non-muscle myosin heavy are still alive, synonymous with median chain 9 gene (NMMHC-A or MYH9) at overall survival 22q11-13 (or 22q12.3-q13.2) mediastinum the central part of the MBL the gene encoding mannose-binding thoracic cavity, between the lungs lectin Medicines Act 1968 a UK Act of McAb monoclonal antibody Parliament which provides the legal MCH mean cell haemoglobin framework governing not only medicines MCHC mean cell haemoglobin concentra- but also the donation, testing, processing tion and issuing of blood components and M-CSF macrophage colony-stimulating products factor Medicines Control Agency a UK MCV mean cell volume organization that, among other duties, MDR multidrug resistance licences transfusion centres to prepare and MDS myelodysplastic syndrome or syn- provide blood components and products dromes medulla (i) the central part of a bone MDS1 a gene, Myelodysplasia Syndrome composed of an anastomosing network 1; gene map locus 3q26; this gene was pre- of trabecular or cancellous bone (ii) the viously thought to be an exon of EVI1, central part of the kidney (iii) the central but is widely expressed both as a unique part of a lymph node (iv) the central part transcript and as a normal fusion tran- of the thymus script with EVI1; encodes a protein of medullary cavity the spaces between unknown function; MDS1 can contribute the trabeculae of medullary bone occu- to an AML1-MDS1 fusion oncogene in pied by fatty or haemopoietic marrow acute myeloid leukaemia, myelodysplas- MEFV the gene encoding pyrin or mareno- tic syndromes and blast crisis of chronic strin, a protein expressed in myeloid granulocytic leukaemia associated with cells and up-regulated during differentia- t(3;21)(q26;q22) tion; strongly expressed in neutrophils mean the average and monocytes and thought to regulate mean cell haemoglobin (MCH) the phagocyte-induced inflammation; muta- average amount of haemoglobin in an tions in this gene can result in familial individual’s erythrocytes Mediterranean fever mean cell haemoglobin concentra- megakaryoblast the earliest recogniz- tion (MCHC) the average concentra- able cell of megakaryocyte lineage HAE-M 01/13/2005 05:13PM Page 159

metastasis 159

megakaryocyte a giant bone marrow meningeal leukaemia infiltration of cell, generally polyploid, of myeloid line- leukaemic cells into the meninges age which produces platelets by frag- meninges the membranes covering the mentation of its own cytoplasm brain and spinal cord megaloblast an erythroblast of larger meningitis inflammation of the meninges, than normal size showing retarded nuclear often caused by bacterial or viral infection maturation in relation to cytoplasmic menorrhagia heavy menstrual bleeding, maturation may result from a haemostatic defect and megaloblastic a term indicating abnor- may lead to iron deficiency anaemia mal haemopoiesis in which there is MER2 a gene at 11p15.5 that encodes delayed nuclear development leading antigens of the MER2 or RAPH blood to large haemopoietic cells and erythro- group systems cytes, and dissociation between nuclear M:E ratio myeloid:erythroid ratio and cytoplasmic maturation (see also mercaptopurine an antimetabolite used giant metamyelocyte) in the maintenance treatment of acute megaloblastic anaemia anaemia with lymphoblastic leukaemia megaloblastic haemopoiesis messenger ribonucleic acid (messen- meiosis the process in which chromo- ger RNA, mRNA) ribonucleic acid somes of a cell replicate followed by two that is transcribed in the nucleus, on a nuclear divisions so that the complement DNA template, and moves to the cyto- of chromosomes in the resultant cells is plasm, becoming attached to ribosomes halved; the process by which germ cells and serving as a template for synthesis are produced of proteins MEL1 a gene, PR Domain-containing metabolic acidosis acidosis other than protein 16, PRDM16, also known as that due to accumulation of carbonic acid MDS1/EVI1-Like gene 1, gene map locus metabolic rate the rate of energy expen- 1p36.6, encodes a PR zinc finger protein diture by the body similar to MDS1, which is transcription- metabolism the aggregate of chemical ally activated, probably by proximity process occurring in a living organism; to the ribophorin 1 gene, RPN1, at 3q21 includes anabolism, in which complex in myelodysplastic syndrome and acute molecules and tissues are built up, and myeloid leukaemia associated with catabolism, in which tissues, cells and t(1;3)(p36;q21) complex molecules are broken down melaena black faeces, indicative of the metachromatic staining uptake of a presence of altered blood following hae- dye by a cell component with the dye then morrhage into the upper gastrointestinal altering its colour tract metamyelocyte a late, non-dividing melanocyte a pigmented skin cell found cell in granulocyte maturation; it is in the lower epidermis derived from a myelocyte and matures melanoma a tumour of cells analogous to a band cell (see Fig. 25, p. 95) to normal melanocytes; use of this term metaphase the third of the five stages is often restricted to malignant tumours of mitosis in which the chromosomes of melanocyte lineage become arranged around the equatorial melphalan an alkylating agent used in plane of the mitotic spindle with their the treatment of multiple myeloma and centromeres being attached to the spindle; certain other tumours the stage of nuclear division that is opti- memory cell a long-lived B cell or T cell mal for the examination of chromosomes that has already been exposed to an anti- (see Fig. 6, p. 14) gen and can participate in a second- metarubricyte a name proposed for late ary immune response following further erythroblasts exposure to the antigen metastasis (i) the process by which a MEN an alternative name for ELL tumour spreads to distant parts of the HAE-M 01/13/2005 05:13PM Page 160

160 metastatic

body (ii) a deposit of tumour at a site of synthetic oligonucleotides arrayed on distant from the primary tumour a microchip metastatic able to metastasize or having microcyte an abnormally small metastasized erythrocyte methaemalbumin a breakdown prod- microcytic anaemia anaemia charac- uct of oxidized haemoglobin that has terized by microcytosis been bound to albumin; the Schumm’s microcytosis the presence of abnorm- test detects methaemalbumin and a posit- ally small erythrocytes ive result gives evidence of intravascular microfilaments 7 nm diameter fila- haemolysis ments composed mainly of actin and methaemoglobin oxidized haemoglobin actin-binding proteins that form part of methaemoglobinaemia an increased the cytoskeleton of cells proportion of methaemoglobin in microfilaria the stage of the life cycle of erythrocytes filaria which is identified by peripheral methotrexate an antimetabolite that blood examination, the prelarval form of interferes with folic acid metabolism, the parasite used in the maintenance treatment of microgram (µg) one millionth of a acute lymphoblastic leukaemia, in certain gram, 1 × 10–6 of a gram solid tumours and as an immunosuppres- microhaematocrit a haematocrit deter- sive agent mination performed in a capillary tube methylene blue a dye or stain which microlitre (µl) a millionth (10–6) of a can be used as a component of a litre Romanowsky stain and also for staining micromegakaryocyte a megakaryocyte reticulocytes and Heinz bodies; however, no more than 30 microns in diameter it should be noted that new methylene micromole (µmol) a millionth (10–6) of blue rather than methylene blue should a mole be used for staining haemoglobin H micron (µ) a millionth (10–6) of a metre inclusions microscope an instrument with a num- methylene tetrahydrofolate reduc- ber of lenses for the visual examination of tase an enzyme involved in folic acid small objects metabolism; deficiency, resulting from microscopic (i) very small (ii) pertaining homozygosity for a thermolabile variant, to a microscope is present in 5% of the population and microscopy examination by means of a is associated with an increased risk of microscope thrombosis microspherocyte a spherocyte which MGG May–Grünwald–Giemsa (stain) is smaller than a normal erythrocyte, MGUS monoclonal gammopathy of unde- formed by red cell fragmentation or by termined significance removal of parts of the erythrocyte mem- MHC major histocompatibility complex brane by splenic macrophages MIC the Morphologic-Immunophenotypic- microtubules polymers of tubulin, with Cytogenetic classification of leukaemias a diameter of about 24 nm, that form part MIC-M the Morphological-Immuno- of the cytoskeleton; among other func- phenotypic-Cytogenetic-Molecular genetic tions, they form the mitotic spindle classification of leukaemias miliary tuberculosis disseminated microangiopathic haemolytic an- tuberculosis with granulomas distributed aemia (MAHA) haemolytic anaemia through many organs caused by pathological processes, either milligram (mg) one thousandth part endothelial damage or fibrin deposition, (10–3) of a gram operating in small blood vessels millilitre (ml) one thousandth part (10–3) microarray analysis a method of of a litre assessing the RNA expression profile millimole (mmol) one thousandth part of a single tissue or cell line by means (10–3) of a mole HAE-M 01/13/2005 05:13PM Page 161

MLL 161

min a cytogenetic abbreviation for a mitotic spindle the microtubules to which minute chromosome chromosomes attach during metaphase minimal residual disease (MRD) the mitozantrone an anti-cancer drug presence of small numbers of neoplastic related to the anthracyclines, used in the cells, detectable by techniques such as treatment of lymphomas immunophenotyping or molecular genetic MKL1 a gene, Megakaryoblastic Leuk- analysis, in bone marrow or blood sam- aemia 1, also known as MAL, gene map ples in which no such cells are detectable locus 22q13; encodes a nuclear protein by microscopic examination; minimal containing a single SAP DNA-binding residual disease can be defined as the motif; MKL1 contributes to RBM15- lowest level of residual disease detectable MKL1 and MKL1-RBM15 fusion genes by available methods in acute megakaryoblastic leukaemia of minute chromosome (min) an acen- infants with t(1;22)(p13;q13); it is the tric fragment of a chromosome, smaller RBM15-MKL1 fusion gene (also known than the width of a single chromatid as OTT-MAL) which is likely to be (double minute chromosomes are acen- oncogenic (see also MAL, OTT ); the tric and atelomeric chromatin bodies fusion protein retains all functional composed of circular DNA) motifs encoded by each gene including miscarriage a spontaneous abortion an oligomerization domain in MKL1 mis-sense mutation a mutation that MLF1 a gene, Myeloid Leukaemia Factor results in the encoding of a different 1, gene map locus 3q25.1, encodes a amino acid widely expressed protein of unknown mitochondrial pertaining to mitochondria function which has been observed in the mitochondrial cytopathy an inherited cytoplasm and in the nucleus in discrete disorder transmitted by genes on a cir- bodies; MLF1 contributes to the NPM- cular mitochondrial chromosome, rather MLF1 fusion gene in acute myeloid than by genes located on nuclear leukaemia or myelodysplastic syndrome chromosomes associated with t(3;5)(q25.1;q34) mitochondrion (plural mitochondria) MLL a gene, Mixed Lineage Leukaemia, a rod or oval-shaped organelle enclosed also known as Myeloid-Lymphoid by two membranes with the inner mem- Leukaemia gene, HRX, ALL-1 and Htrx- brane being folded into cristae which pro- 1, gene map locus 11q23, encodes a multi- ject into the matrix of the mitochondrion; domain protein with some homology to the mitochondrion is the major site of the Drosophila transcriptional regulator, energy production and has enzymes trithorax, which positively maintains the responsible for part of the haem synthesis expression of multiple homeobox genes pathway (see Fig. 34, p. 116) during development; MLL is fused to a mitogen an agent that promotes mitosis great variety of other genes in acute mitomycin C an antitumour antibiotic myeloid leukaemia, acute lymphoblastic which can cause microangiopathic haemo- leukaemia and acute biphenotypic leuk- lytic anaemia aemias; important functional domains mitosis the process of cell division in include the AT hook (mediates DNA which chromosomes replicate before cell binding to AT-rich DNA sequences, division; daughter cells therefore have the phosphorylated in mitosis), subnuclear same complement of chromosomes as the localization domains (SNLs, areas of high parent cell (see Fig. 6, p. 14) homology to trithorax), CxxC motifs mitotic figure chromosomes visible (mediate interaction with transcriptional during the process of mitosis repressors), PHD zinc fingers (mediate mitotic index the proportion of cells in interaction with nuclear cyclophilins), mitosis transactivation domain and SET domains; mitotic rate the rate at which cells enter fusion proteins always retain the amino mitosis terminus of MLL (which carries the AT HAE-M 01/13/2005 05:13PM Page 162

162 MMSET

hook, SNL and CxxC motifs), and con- with acute myeloid leukaemia associated sistently lose the PHD, transactivation with trisomy 11 and in some with normal and SET domains, which are replaced by cytogenetics and is amplified in some sequences of partner genes; MLL trans- patients with complex chromosomal location breakpoints almost invariably rearrangements—in some of these lie within an 8.3 Kb breakpoint cluster patients MLL is found at multiple sites region (bcr) which corresponds to a on the genome and in others the amplified nuclear matrix attachment region and is gene has been located specifically in a ring susceptible to DNA cleavage in response chromosome, in a homogeneously stain- to topoisomerase II inhibitors (e.g. ing region or in double minute chromo- etoposide) or apoptosis; there are at least somes; duplication or amplification of a 28 reported partner genes for MLL in non-rearranged MLL gene is common leukaemia; fusion genes to which MLL in therapy-related myelodysplastic syn- contributes include: dromes and acute myeloid leukaemia • MLL-AF1p in t(1;11)(p32;q23) and is closely related to prior alkylat- • MLL-AF1q in t(1;11)(q21;q23) ing agents and to TP53 mutations (which • MLL-LAF4 in t(2;11)(p15;p14) may be the cause of the duplication/ • MLL-LPP and LPP-MLL in amplification); partial amino terminal t(3;11)(q28;q23) duplications of MLL due to genomic • MLL-GMPS in t(3;11)(q25;q23) rearrangements have been reported in • MLL-AF4 in t(4;11)(q21;q23) acute myeloid leukaemia and B-lineage • MLL-GRAF in t(5;11)(q31;q23) acute lymphoblastic leukaemia, and carry • MLL-AF5q31 in ins(5;11) a poor prognosis; deletions of exon 8 of (q31;q13q23) MLL (encoding the first PHD domain) • MLL-AF6q21 in t(6;11)(q21;q23) have been reported in T-lineage acute • MLL-AF6q27 in t(6;11)(q27;q23) lymphoblastic leukaemia • MLL-AF9 in t(9;11)(p22;q23) MMSET a gene, Multiple Myeloma SET • MLL-AF9q34 in t(9;11)(q34;q22) domain, officially known as WHSC1— • MLL-ABI1 in t(10;11)(p11.2;q23) Wolf-Hirschhorn Syndrome Candidate • MLL-AF10 in t(10;11)(p12;q23) gene 1, gene map locus 4p16.3, encodes • MLL-LARG by interstitial deletion at a SET domain protein; is involved, 11q23 together with FGFR3, in a cryptic • MLL-FBP17 in ins(11;9)(q23;q34) t(4;14)(p16.3;q32.2) translocation, which inv(11)(q13q23) is present in about 20% of cases of • MLL-CALM in inv(q14,2q23.1) multiple myeloma; the mechanism of • MLL-GPNH in t(11;14)(q23;q24) dysregulation is proximity to an intronic • MLL-AF17 in t(11;17)(q23;q21) enhancer on the der(4); Wolf–Hirschhorn • MLL-RARA in t(11;17)(q23;q12) syndrome is a congenital malformation • MLL-EEN in t(11;19)(q23;p13) syndrome associated with hemizygous • MLL-ELL in t(11;19)(q23;p13.1) deletions of 4p—it is unclear whether a • MLL-ENL in t(11;19)(q23;p13.3) single locus is involved in the phenotype • MLL-CBP in t(11;16)(q23;p13.3) —WHSC1 is a candidate gene in the region • MLL-p300 in t(11;22)(q23;q13) MN1 a gene, Meningioma 1, gene map • MLL-hCDCre in t(11;22)(q23;q11.2) locus 22q12.3-qter, encodes a putative • MLL-AFX in t(X;11)(q13;q23) transcriptional activator, was initially • MLL-SEPTIN2 in two cases of AML cloned from a meningioma; MN1 con- with t(X;11;3;11) and ins(X;11)(q24;q23) tributes to an MN1-ETV6 fusion gene in respectively acute myeloid leukaemia associated with MLL is also rearranged in acute t(12;22)(p13;q11); unusually for leukae- myeloid leukaemia associated with mogenic fusion proteins involving ETV6, t(8;11)(q24;q23) and t(10;11)(q22;q23); the MN1-ETV6 fusion protein lacks a MLL is reduplicated in some patients functional ETV6 PNT (oligomerization) HAE-M 01/13/2005 05:13PM Page 163

MOZ 163

domain—the mechanism of transforma- monocytopenia a low blood monocyte tion is unclear count MNS a red cell-specific blood group sys- monocytosis an increase in the number tem, the relevant antigens being encoded of monocytes in the blood by GYPA (M and N) and GYPB (S and s) monomer a molecule that combines with and being expressed on glycophorins A other similar molecules to form a polymer and B respectively mononuclear cell literally a cell with one molar solution a solution containing nucleus but in practice this term is used one mole per litre to indicate a lymphocyte or a monocyte mole the amount of a pure substance monosomy the presence in a cell or a containing the same number of chemical clone of cells of only a single copy of a units as there are atoms of carbon in chromosome of which there are normally exactly 12 grams of carbon12 (i.e. 6.023 × two copies 1023, Avogadro’s number) monosomy 7 syndrome a myelodys- molecular genetic analysis analysis of plastic syndrome of infancy, now included DNA or RNA, analysis of genes in the category juvenile myelomonocytic molecule the smallest unit of a chemical leukaemia of the WHO classification substance, formed from atoms monozygotic arising from a single monoblast a blast cell of monocyte zygote, e.g. monozygotic twins lineage, found in acute myelomono- MORF a gene, Monocytic leukaemia zinc cytic leukaemia and acute monocytic/ finger protein-Related Factor; gene map monoblastic leukaemia (FAB AML cat- locus 10q22; encodes a ubiquitously egories M4 and M5) expressed histone acetylase related to monoclonal relating to a single clone MOZ; that contributed to MORF-CBF monoclonal antibody (McAb) an and CBF-MORF fusion genes in a child antibody produced by a clone of lym- with M5 acute myeloid leukaemia phoid cells morphology the study of the appear- monoclonal antibody-specific immo- ance of cells or tissues of higher or lower bilization of platelet antigens organisms (MAIPA) a test for anti-platelet Morquio’s disease an inherited metabolic antibodies disorder, type IV mucopolysaccharidoses monoclonal gammopathy a neoplas- mortality rate the rate of death, usually tic disorder in which a monoclonal expressed as the number of deaths per immunoglobulin or part of an immuno- 100 000 of population per year globulin in synthesized morular cell a cell of plasma cell lineage monoclonal gammopathy of unde- containing multiple vacuoles, named termined significance (MGUS) the because it is considered to resemble a presence of a serum paraprotein but with- mulberry; a Mott cell out the criteria for a diagnosis of multiple mosaic an individual with two distinct myeloma being met, previously known as cell lines arising from a single zygote benign monoclonal gammopathy Mott cell a cell of plasma cell line- monoclonal lymphocytes lymphocyte age containing multiple vacuoles, see also derived from a single precursor morular cell monoclonal proliferation increased mouse-rosette forming cell (MRFC) numbers of lymphoid (or other) cells a lymphocyte able to form rosettes with belonging to a single clone, usually indic- mouse erythrocytes, an early test for chronic ative of neoplasia lymphocytic leukaemia used before mono- monocyte a mature cell of monocyte/ clonal antibodies became available macrophage lineage, derived from a MOZ a gene, Monocytic leukaemia Zinc promonocyte and maturing into a tissue finger, officially known as Zinc Finger macrophage protein 220 (ZNF220), gene map locus monocytic pertaining to monocytes 8p11; leukaemogenesis mediated by HAE-M 01/13/2005 05:13PM Page 164

164 MPD

fusion gene products may be related to from proximity to the TCRB gene as a aberrant chromatin acetylation; MOZ result of t(X;7)(q28;q35) fuses with: MTG8 an alternative designation of • part of the CBP oncogene to form ETO both MOZ-CBP and CBP-MOZ in M5 MTG16 a gene, Myeloid Translocation acute myeloid leukaemia associated Gene on chromosome 16, also known with t(8;16)(p11;p13) as Core-Binding Factor, Alpha subunit • part of the TIF2 oncogene to form 2, Translocated to, 3, CBFA2T3, gene the MOZ-TIF2 fusion gene in acute map locus 16q24, a homologue of myeloid leukaemia associated with MTG8 (ETO); a widely expressed gene, inv(8)(p11q13) it encodes 2 proteins which differ at • part of the p300 gene to form both their amino termini both of which carry MOZ-p300 and p300-MOZ fusion genes 4 nervy zinc ﬁnger domains; MTG16 in M5 acute myeloid leukaemia associ- is rearranged and translocated to the ated with t(8;22)(p11;q13) CBFA2 locus in t(16;21)(q24;q22) associ- MPD myeloproliferative disorder ated with therapy-related acute myeloid MPL a gene, Myeloproliferative Leuk- leukaemia; analogous to the CBFA2/ aemia virus gene homologue, gene map MTG8 (ETO) fusion protein, the CBFA2/ locus 1p34, encodes the receptor for MTG16 chimaera comprises the runt thrombopoietin, a truncated homologue domain of CBFA2 fused to almost the of v-mpl which is an oncogene of a murine entire coding region of MTG16 retrovirus; germline mutations in MPL MTS1 see CDKN2A are associated with congenital amega- MUC1 a gene, transmembrane Mucin 1, karyocytic thrombocytopenia also known as Polymorphic Epithelial MPO the gene at 17q23.1 encoding neu- Mucin (PEM) and Peanut reactive trophil myeloperoxidase Urinary Mucin (PUM), gene map locus MPO myeloperoxidase 1q21, encodes an epithelium-speciﬁc M-protein a largely disused term for a mucin which is often overexpressed in paraprotein carcinoma of the breast and is a target for MRD minimal residual disease the monoclonal antibodies HMFG-1, MRFC mouse-rosette forming cell HMFG-2 and SM-3, used to detect solid MRI magnetic resonance imaging tumour associated antigens; there is a mRNA messenger ribonucleic acid series of tandem repeats which consti- MSF a gene, MLL Septin-like Fusion tutes much of the coding region of the gene, gene map locus 17q25, encoding gene, with marked allelic variation due to a protein of the septin family; MSF variation in their number—consequently, fused to MLL in a child who developed MUC1 is a locus used for VNTR (vari- therapy-related acute myeloid leukaemia able number of tandem repeats) analysis; with t(11;17)(q23;q25) MUC1 is rearranged and over-expressed MTCP1 a gene, Mature T-Cell in B-cell non-Hodgkin’s lymphoma asso- Proliferation 1, gene map locus Xq28, ciated with t(1;14)(q21;q32), as a result of encodes two entirely different proteins, being brought into proximity to the IGH p8MTCP1 and p13MTCP1, which are gener- enhancer; also overexpressed in epithelial ated by alternative splicing; p13MTCP1 has tumours structural homology with TCL-1, which mucin a mucopolysaccharide secreted is more often involved in this type by mucous glands of leukaemia; p8MTCP1 is a cysteine- mucopolysaccharidoses a group of rich mitochondrial protein of uncertain inherited metabolic disorders in which function; MTCP is juxtaposed to the there is abnormal accumulation of TCRAD (αδ) locus at 14q11 in some mucopolysaccharides cases of T-prolymphocytic leukaemia mucosa mucous membrane, lining of the with t(X;14)(q28;q11), leading to its over- gastrointestinal, respiratory and geni- expression; activation can also result tourinary tracts HAE-M 01/13/2005 05:13PM Page 165

MYC 165

mucosa-associated lymphoid tissue Figure 54 Multiple myeloma. (MALT) lymphoid tissue associated with Laboratory investigations in multiple myeloma. mucous membranes such as the pharynx, Scanning densitometry of an electrophoretic strip γ larynx, bronchi and small intestine (top) showing two bands in the early region (arrow) and late γ region (arrowheads) respectively. The mucous membrane mucosa, the lining corresponding electrophoretic strip is shown in the of the gastrointestinal, respiratory and left lane (bottom). Immunofixation shows a single genitourinary tracts band identifiable with anti-γ (lane 2) and two bands MUD matched unrelated donor (note: identifiable with anti-λ (lane 6); the patient therefore λ λ volunteer unrelated donor (VUD) is now has an IgG paraprotein and a Bence Jones protein the preferred terminology) in the serum. Serum Bence Jones protein is seen in the serum in patients with multiple myeloma and multidrug resistance (MDR) genetic- renal failure. ally-based resistance of cells to the actions of multiple anti-cancer drugs multiple myeloma a disseminated plasma cell neoplasm affecting predominantly the bone marrow, most cases being characterized by synthesis of a monoclonal immunoglobulin, a Bence Jones protein or both (Fig. 54); in the WHO classification it is designated ‘plasma cell myeloma’ multiplex PCR a PCR reaction using a number of pairs of primers so that a number of DNA segments can be amplified simultaneously multipotent myeloid stem cell a haemopoietic stem cell capable of giving rise to all myeloid lineages, also know as the common myeloid progenitor MUM1 see IRF4 MUM2/3 see IRTA1 and IRTA2 murine relating to the mouse mutagen an agent capable of causing mutation mutagenic a description of an agent that can cause mutation mutation a structural alteration in the DNA of a cell, either a germ cell or a somatic cell, which can be transmitted to the fertilized gamete or to the progeny etic cells, its expression declining as they of the somatic cell differentiate; the first intron of MYB MYB a gene, avian Myeloblastosis viral contains two interferon-responsive regu- oncogene homologue, gene map locus latory elements; c-MYB protein is over- 6q22, encodes a transcriptional activator expressed in oestrogen-receptor positive protein, c-MYB, with sequence-specific breast cancer; b-MYB is constitutively DNA-binding activity, that is expressed phosphorylated by cyclin A1 in cases in haemopoietic precursor cells; archety- of acute myeloid leukaemia that over- pal member of a small family of related express CCNA1 genes including a-MYB (at 8q22, ex- MYC a gene, avian Myelocytomatosis pressed in germ cells and breast tissue) viral oncogene homologue, gene map and b-MYB (at 20q13.1, ubiquitously locus 8q24.12, encodes three widely expressed); the c-MYB protein plays a expressed basic helix–loop–helix-leucine key role in cell cycle control in haemopoi- zipper transcription factors derived from HAE-M 01/13/2005 05:13PM Page 166

166 Mycobacterium

alternative translational start sites on the and detached nuclear fragments in cells same mRNA (known as 62KD c-MYC, of neutrophil lineage 64KD c-MYC and S-MYC); all three Mycoplasma a genus of micro- proteins are inactive as monomers or organisms that are smaller than bacteria, homodimers and heterodimerize with including Mycoplasma pneumoniae which MAX to bind target DNA sequences can cause atypical pneumonia, often with known as E-boxes; they are involved an associated cold agglutinin in the activation of genes involved in mycosis fungoides a cutaneous T-cell cellular proliferation and the inhibition neoplasm with formation of cutaneous of growth inhibitory genes; c-MYC is tumours composed of lymphoma cells the archetypal member of a family of myeloblast the earliest morphologically related MYC proteins which are char- recognizable cell of the granulocyte line- acterized by an amino-terminal ‘MYC ages (see Fig. 25, p. 95) box’ domain involved in the recruitment myelocyte an intermediate cell in granu- of histone acetylases; MYC is dysregu- locyte maturation, derived from a pro- lated and contributes to oncogenesis in myelocyte and undergoing two cycles of the following circumstances: mitosis before maturing into a meta- • in Burkitt’s lymphoma and L3 acute myelocyte (see Fig. 25, p. 95) lymphoblastic leukaemia when it comes myelodysplasia morphologically abnor- into proximity to the enhancers of the mal myeloid maturation IGH gene in t(8;14)(q24;q32), the κ gene myelodysplastic syndrome or syn- in t(2;8)(p12;q24) or the λ gene in dromes (MDS) a group of related t(8;22)(q24;q11) neoplastic disorders that have in common • in T-lineage acute lymphoblastic that haemopoiesis is morphologically leukaemia when it comes into proximity dysplastic and functionally ineffective; to the enhancer of the genes of the MDS may evolve into AML; in the WHO TCRAD (αδ) locus in t(8;14)(q24;q11) classification designated as shown in In each case, the unmutated MYC is Table 13 (see also Fig. 55, p. 168) transcriptionally silent; in Burkitt’s lym- myelofibrosis fibrosis of the bone phoma, translocation breakpoints occur marrow; this term is best restricted in the first intron and exon of c-MYC to a bone marrow that shows collagen (class I, sporadic Burkitt’s lymphoma), deposition, not merely increased re- immediately 5′ to c-MYC (class II) or ticulin; the latter is better referred to as several hundred Kb 5′ to c-MYC (class ‘reticulin fibrosis’ or ‘increased reticulin III, endemic Burkitt’s lymphoma); the deposition’ immunoglobulin gene breakpoint is in myelogenous pertaining to bone mar- the VDJ region in endemic Burkitt’s lym- row haemopoietic cells phoma, but in a class switch region in myeloid (i) pertaining to the bone sporadic and HIV-associated Burkitt’s marrow (ii) pertaining to granulocyte– lymphoma; most translocated MYC genes monocyte lineages carry additional point mutations or small myeloid:erythroid ratio (M:E ratio) deletions, typically at the boundary of the ratio of cells of granulocyte–mono- intron 1 and exon 1 and result from cyte lineage to cells of erythroid lineage in somatic hypermutation (see Fig. 46, p. the bone marrow 135); MYC is amplified, uncommonly, in myeloid metaplasia the occurrence of acute myeloid leukaemia haemopoiesis at extramedullary sites; Mycobacterium a genus of micro- myelofibrosis with myeloid metaplasia is organisms including those that cause an alternative designation of idiopathic tuberculosis and leprosy myelofibrosis mycophenolate mofetil an immuno- myelokathexis an inherited disorder in suppressive drug that can cause neu- which neutrophils have long filaments tropenia, hypolobulation of neutrophils separating lobes HAE-M 01/13/2005 05:13PM Page 167

myeloproliferative-myelodysplastic disorder 167

Table 13 The WHO classiﬁcation of myelodysplastic syndromes (MDS)*.

Disease Peripheral blood ﬁndings Bone marrow ﬁndings

Refractory anaemia Anaemia, blasts rarely seen Dysplasia confined to erythroid (RA) and always less than 1% lineage, < 5% blasts, < 15% ringed sideroblasts Refractory anaemia Anaemia, no blasts Dysplasia confined to erythroid with ringed sideroblasts lineage, < 5% blasts, ≥ 15% ringed (RARS) sideroblasts Refractory cytopenia Cytopenias (bicytopenia Dysplasia in ≥ 10% of the cells of with multilineage or pancytopenia), no or two or more myeloid cell lineages, dysplasia (RCMD)† rare blasts, no Auer rods, < 5% blasts, < 15% ringed < 1 × 109/l monocytes sideroblasts, no Auer rods Refractory cytopenia Cytopenias (bicytopenia Dysplasia in ≥ 10% of the cells of with multilineage or pancytopenia), no or two or more myeloid cell lineages, dysplasia and ringed rare blasts, no Auer rods, < 5% blasts, ≥ 15% ringed sideroblasts (RCMD-RS)† < 1 × 109/l monocytes sideroblasts, no Auer rods Refractory anaemia Cytopenias, < 5% blasts, Unilineage or multilineage with excess blasts 1 no Auer rods, < 1 × 109/l dysplasia, 5–9% blasts, no Auer rods (RAEB-1)† monocytes Refractory anaemia Cytopenias, 5–19% blasts, Unilineage or multilineage with excess blasts 2 Auer rods sometimes dysplasia, 10–19% blasts, Auer rods (RAEB-2)† present, < 1 × 109/l sometimes present monocytes Myelodysplastic Cytopenias, no or rare blasts, Unilineage dysplasia, < 5% blasts. syndrome-unclassified no Auer rods No Auer rods (MDS-U)† MDS associated with Anaemia, platelet count Megakaryocytes in normal or isolated del(5q) usual normal or elevated, increased numbers but with < 5% blasts hypolobated nuclei, < 5% blasts, no Auer rods

* Reproduced from Bain BJ, Leukaemia Diagnosis, 3rd edn, Blackwell Publishing, Oxford, 2003. † If cases are therapy-related, this should be speciﬁed and it should be further speciﬁed whether cases are alkylating agent-related (the majority) or topoisomerase II-interactive drug-related (a small minority).

myeloma a tumour composed of cells of myelophthisic anaemia a little used plasma cell lineage (see multiple myeloma) term for leucoerythroblastic anaemia myelomatosis an alternative designa- myeloproliferative disorder (MPD) a tion of multiple myeloma neoplastic conditions in which there is myeloperoxidase the peroxidase iso- expansion of at least one myeloid line- enzyme in cells of granulocyte and mono- age with retention of normal maturation so cyte lineages, neutrophil myeloperoxidase that increased numbers of mature end being encoded by the MPO gene cells are produced (Table 14) (see also myeloperoxidase deficiency a defi- Fig. 55) ciency of neutrophil myeloperoxidase, myeloproliferative-myelodysplastic dis- resulting from a mutation in the MPO order a WHO category of haematological gene; deficiency is usually asymptomatic neoplasms encompassing cases with both but in people with diabetes mellitus can myeloproliferative and myelodysplastic lead to disseminated candidiasis features (Fig. 55) HAE-M 01/13/2005 05:13PM Page 168

168 myelosclerosis

Figure 55 the relationship between the myelodysplastic and myeloproliferative disorders. A diagrammatic representation, based on the WHO classiﬁcation, showing the myeloproliferative disorders, the myelodysplastic syndromes and the ‘overlap’ myelodysplastic/myeloproliferative disorders.

MDS MPD MDS/ RA CML RARS MPD CNL RCMD CEL CMML RCMD-RS PV aCML RAEB IM JMML 5q– syndrome ET Unclassified Unclassified Unclassified

AML

Table 14 The WHO classiﬁcation of the chronic myeloproliferative disorders.

Chronic myelogenous leukaemia, Philadelphia chromosome positive (t(9;22)(q34;q11), BCR-ABL fusion) Chronic neutrophilic leukaemia Chronic eosinophilic leukaemia/hypereosinophilic syndrome Chronic idiopathic myeloﬁbrosis Polycythaemia vera Essential thrombocythaemia Myeloproliferative disorders, unclassiﬁable

myelosclerosis an alternative designa- Smooth Muscle Myosin Heavy Chain tion of myeloﬁbrosis gene, gene map locus 16p13.13; part of myelosuppression inhibition of hae- MYH11 fuses with part of CBFB at mopoiesis 16q22 in M4Eo acute myeloid leukaemia myeov a gene, Myeloma overexpressed associated with inv(16)(p13q22) and gene, gene map locus 11.q13, encodes a t(16;16)(p13;q22) putative RNA-binding protein with a myocardial infarction infarction of hydrophobic carboxy terminal tail char- cardiac muscle, usually resulting from acteristic of cytoplasmically exposed coronary occlusion; haematological effects membrane proteins; overexpressed, include neutrophilia and an increase in the together with cyclin D1, in a subset of erythrocyte sedimentation rate cell lines with t(11;14)(q13;q32) derived myxoedema hypothyroidism; haema- from patients with multiple myeloma tological effects include anaemia, macro- MYH11 a gene, Myosin Heavy chain cytosis and the presence of acanthocytes gene 11, also known as SMMHC— HAE-N 01/13/2005 05:14PM Page 169

NAD nicotine adenine dinucleotide directed at cellular antigens; the latter NADP nicotine adenine dinucleotide NK activity is usually overruled by a phosphate killer-inhibitory receptor that recognizes naïve lymphocyte a T or B lymphocyte MHC type I molecules on normal body that has not yet encountered antigen cells nanogram one thousandth millionth of natural killer cell leukaemia a a gram, 1 × 10–9 of a gram leukaemia of cells analogous to natural NAP neutrophil alkaline phosphatase killer cells, which may or may not retain NAP score a summation of the grading natural killer function of neutrophil alkaline phosphatase activity naturally occurring antibody a blood in 100 neutrophils group antibody that develops without naphthol AS acetate esterase (NASA) exposure to the corresponding red cell a non-specific esterase activity character- antigen istic on the monocyte lineage naturally occurring anticoagulants naphthol AS-D acetate esterase a collective name for protein C, protein S, (NASDA) a non-specific esterase activity antithrombin and tissue factor pathway characteristic of the monocyte lineage inhibitor (Fig. 56) naphthol AS-D chloroacetate NBS1 a gene at 8q21, Nijmegen Breakage esterase (chloroacetate esterase, Syndrome 1, that is mutated in the CAE) esterase activity specific for neu- Nijmegen breakage syndrome; encodes a trophils (and mast cells) forkhead domain protein, nibrin, which is NASA esterase naphthol AS acetate part of the ‘BRCA1-associated genome esterase surveillance complex’, involved in the NASDA esterase naphthol AS-D acetate detection and repair of abnormal DNA esterase structures National External Quality Assurance NCCLS National Committee for Clinical Scheme (NEQAS) a UK based Laboratory Standards (USA) national quality assurance scheme for NCF1 a gene at 7q11.23 encoding pathology laboratories Neutrophil Cytosolic Factor 1 (p47— National Institute of Clinical phox), mutation of which can lead to Excellence (NICE) a body set up to chronic granulomatous disease assess new treatments, compile clinical NCF2 a gene at 1q25 encoding Neutrophil guidelines and facilitate introduction of Cytosolic Factor 2 (p67—phox), muta- cost effective treatments (UK) tion of which can lead to chronic granulo- natural killer cell (NK cell) a lymphomatous disease cyte which has Fc receptors and can kill NCI National Cancer Institute (USA) cells by antibody-dependent cellular cyto- neonatal alloimmune thrombocy- toxicity (ADCC) but is also capable of topenia intrauterine or neonatal direct killing of cells, e.g. virus-infected thrombocytopenia resulting from trans- cells or tumour cells, without a require- placental passage of maternal platelet ment for the presence of an antibody alloantibodies

169 HAE-N 01/13/2005 05:14PM Page 170

170 neoplasia

Figure 56 Naturally occurring anticoagulants. The naturally occurring anticoagulants and inhibitors of coagulation. Positive effects are shown by an arrow and negative effects by a crossed arrow. Plasma contains two naturally occurring anticoagulants, antithrombin (AT) and tissue factor pathway inhibitor (TFPI). AT inhibits all the serine proteases of the coagulation network— XIIa, XIa, IXa, Xa and IIa (thrombin); its action is greatly enhanced by heparin or by heparin-related molecules on the surface of cells. TFPI, both that present in plasma and that released by activated platelets, inhibits tissue factor (TF), VIIIa and Va. The generation of thrombin leads to activation of other naturally occurring anticoagulants. Thrombin binds to thrombomodulin, a receptor on endothelial cells, and the complex activates protein C (PC) to activated protein C (APC), which is a serine protease capable of destroying factors VIIIa and Va. The action of APC is enhanced by protein S (PS), which binds PC to the platelet surface. AT and TFPI are both synthesized in endothelial cells.

AT TFPI XII XIIa

AT TF + VII XI XIa

TF – VIIa AT IX IXa TFPI VIIIa Phl Ca AT

PS XXa TFPI Va Phl Ca AT PS II IIa

APC Fibrinogen Fibrin

PC (bound to PC receptor) Thrombin– thrombomodulin complex

neoplasia the process by which neo- nephrotic syndrome fluid retention plasms develop and oedema as a consequence of neoplasm literally a ‘new growth’ or hypoalbuminaemia caused by heavy tumour; in modern usage proliferation proteinuria of a population of cells derived from a NEQAS National External Quality genetically altered precursor cell leading Assurance Scheme to formation of a solid tumour, such as a neuroblastoma a malignant tumour of carcinoma, or to leukaemia or a related neuroendocrine origin occurring mainly condition in children neoplastic pertaining to a neoplasm neurofibromatosis an inherited con- nephritis inflammation of the kidneys dition characterized by multiple HAE-N 01/13/2005 05:14PM Page 171

NFκB2 171

neurofibromas and small areas of skin encodes a member of the Serpin super- pigmentation (café au lait spots); there family, an important physiological reg- is an increased incidence of juvenile ulator of thrombin in tissues; PN1 myelomonocytic leukaemia (including forms 1:1 (stoichiometric) complexes monosomy 7 syndrome) (see also NF1) with thrombin which are removed by neuronal lipofuscinosis (Batten’s dis- cellular endocytosis ease) an inherited metabolic disorder NF1 a gene, Neurofibromatosis, type which may be a cause of vacuolated bone 1 also known as neurofibromin, gene marrow macrophages map locus 17q11, a candidate tumour neutropenia reduced numbers of neu- suppressor gene, encodes a ubiquitously trophils in the blood expressed GTPase-activating protein neutrophil a granulocyte with neutro- (GAP), which accelerates the hydroly- philic granules, i.e. with granules which sis of GTP by RAS, thereby inactivating are neither strongly acidophilic nor it—loss of NF1 can lead to increased strongly basophilic but take up both RAS activity; alternative splicing of NF1 components of the stain gives rise to at least four isoforms; muta- neutrophil alkaline phosphatase tions of NF1 cause neurofibromatosis (NAP) the isoenzyme of alkaline phos- type 1, in which there is a propensity to phate that is present in a neutrophil the development of juvenile myelomono- neutrophil elastase a protease which cytic leukaemia (often associated with is one of the major constituents of loss of the normal allele) and acute azurophilic granules of neutrophils and myeloid leukaemia; acquired mutations is expressed more weakly in the granules of NF1 are also associated with an of monocytes and macrophages, encoded increased rate of occurrence of juvenile by the ELA gene at 19p13.3; mono- myelomonocytic leukaemia; mutations clonal antibodies to neutrophil elastase are also sometimes present in myelodys- can be used to identify maturing cells plastic syndrome of neutrophil lineage NFκ B1 a gene, Nuclear Factor κ (kappa) neutrophilia increased numbers of neu- B, subunit 1, gene map locus 4q23-q24, trophils in the blood encodes two widely expressed transcrip- neutrophilic leukaemia a chronic tion factors, p50 and p105, that are Philadelphia-negative leukaemia in which activated by a wide range of inflamm- the major cell in the blood is a mature atory signals; NFκB proteins normally neutrophil complex with REL proteins; in the quies- neutrophil leucocytosis increased cent state, the NFκB/REL complex numbers of neutrophils in the blood is sequestered in the cytoplasm by the neutrophil specific granule deficiency inhibitory proteins Iκ B1 and IκB2; inflam- an inherited defect of neutrophil func- matory cytokines promote IκB degradation in which there are bilobed or poorly tion by inducing their phosphorylation, lobulated neutrophils that are deficient thereby allowing the NFκB/REL com- in at least one primary granule protein plex to enter the nucleus and induce and all secondary and tertiary granule transcription (see also TAX) proteins, resulting from mutation in the NFκ B2 a gene, Nuclear Factor κ (kappa)- C/EBPε gene; eosinophil granules also B, subunit 2, also known as LYT10, lack specific proteins gene map locus 10q24; see also NFκB1; new methylene blue a dye or stain encoding p52 and p100 members of which can be used in a Romanowsky stain the REL/NFκB family of transcrip- and also to stain reticulocytes, Heinz bod- tion factors; NFκB2 is involved in ies and haemoglobin H inclusions t(10;14)(q24;q32) which is found in less NEXIN1 a gene, also known as Protease than 1% of cases of diffuse large B-cell Nexin 1 (PN1) and Protease Inhibitor lymphoma but in a somewhat higher per- 7 (PI7); gene map locus 2q33–q35; centage of low grade B-cell lymphoma. HAE-N 01/13/2005 05:14PM Page 172

172 NICE

NICE National Institute of Clinical can be controlled by diet and oral hypo- Excellence glycaemic agents nicotine adenine dinucleotide (NAD) non-random chromosomal abnorm- and nicotine adenine dinucleotide ality (i) a chromosomal abnormal- phosphate (NADP) coenzymes that ity present in a population of cells; as act as electron and hydrogen carriers in defined by the International System of some oxidation-reduction reactions Nomenclature a non-random (or clonal) NIDDM non-insulin dependent diabetes abnormality is present if at least two cells mellitus show the same structural abnormality or Niemann–Pick disease an inherited additional chromosome or if at least three metabolic disorder of which foamy macro- cells show the same chromosomal loss (ii) phages in the bone marrow are one feature a recurring chromosomal abnormality, night sweats heavy nocturnal sweat- often associated with a specific neoplasm ing, characteristic of lymphoma, par- non-reciprocal translocation a trans- ticularly Hodgkin’s disease, but not location in which a segment of one chro- pathognomonic mosome moves to another chromosome NIH National Institutes of Health (USA) but there is no reciprocal transfer Nijmegen breakage syndrome an non-secretor see FUT1 autosomal recessive chromosomal non-secretory myeloma multiple instability syndrome characterized by myeloma in which there is no paraprotein microcephaly, mental retardation, café au in the serum nor any Bence Jones protein lait spots, growth retardation, immuno- in the urine deficiency and cancer predisposition, nonsense mutation a mutation that resulting from mutation in the NBS1 converts a codon from one encoding an gene; associated with an increased incid- amino acid to one that does not encode ence of B-lineage neoplasms and a lesser an amino acid and therefore functions as increase in T-lineage neoplasms a stop codon nitrogen mustard one of the earliest normal distribution having a Gaussian cytotoxic drugs, related to mustard gas or bell-shaped distribution when plotted and previously used in the treatment of as a histogram (see Fig. 45, p. 128) Hodgkin’s disease normal range the range of results of a nitrosourea a group of anti-cancer specific laboratory test expected in a heal- drugs, including BCNU and CCNU, thy population (see also reference range) used in treating lymphomas and solid normoblast an erythroblast showing tumours normoblastic maturation nitrous oxide an anaesthetic gas; heavy normoblastic maturation erythroid exposure can cause megaloblastic maturation in which the nucleus and haemopoiesis as a consequence of inacti- cytoplasm mature synchronously

vation of vitamin B12 normochromic normally staining (of a NK cell natural killer cell red cell) NMR nuclear magnetic resonance (imaging) normocytic of normal size (of a red cell) nomogram a diagram representing the Northern blot a modiﬁcation of a relationship between variables in a given Southern blot, a technique for separating system, e.g. the relationship of surface RNA molecules according to size, for area to height and weight (see Fig. 71, subsequent ‘blotting’ onto a membrane p. 212) or between pounds and kilograms and hybridization: the name is a play on non-Hodgkin’s lymphoma (NHL) any words lymphoma other than Hodgkin’s disease NPM1 a gene, Nucleophosmin/nucleo- (see Tables 10 and 11, pp. 137 and 153) plasmin family, member 1, gene map non-insulin dependent diabetes mel- locus 5q34-35, encodes a nucleolar litus a form of diabetes mellitus with phosphoprotein whose levels increase in onset usually in middle or old age, which normal cells when they are mitotically HAE-N 01/13/2005 05:14PM Page 173

NUP98 173

stimulated; it is involved in the assembly nitrogenous base (a heterocyclic ring con- of ribosomal proteins into ribosomes and taining nitrogen and carbon atoms), a is associated with unduplicated centro- 5-carbon ring-shaped sugar molecule (a somes, and is dissociated from them by pentose) which, in the case of DNA is CDK2/cyclin E-mediated phosphoryla- deoxyribose and in the case of RNA is tion; part of NPM fuses with: ribose, and a phosphate group; a base • part of the RARA gene to form NPM- linked to the pentose group is designated RARA in t(5;17)(q32;q21) associated a nucleoside, which when phosphorylated with M3-like acute myeloid leukaemia; at the 3′ position of the pentose group is the fusion protein exhibits both positive designated a nucleotide; the nitrogenous and negative transcriptional properties bases fall into two classes; purines have • part of the MLF1 oncogene to form fused ﬁve and six member rings and an NPM-MLF1 fusion gene in acute pyrimidines have six member rings myeloid leukaemia or myelodysplastic nucleus that part of a cell, which in- syndrome associated with t(3;5)(q25.1;q34) cludes chromosomal DNA and nuclear • part of the ALK oncogene to form proteins such as histones, enclosed in a an NPM-ALK fusion gene in T-lineage nuclear membrane anaplastic large cell lymphoma associ- NuMA a gene, Nuclear Mitotic ated with t(2;5)(p23;q35); it can then Apparatus, gene map locus 11q13; shuttle NPM-ALK to the nucleus encodes a nuclear protein that localizes NSD1 a gene, Nuclear receptor-binding to the spindle apparatus during mitosis; Su-var, enhancer of zeste, and trithorax contributes to the NuMA-RARα fusion Domain protein 1, also known as SET gene in M3-like acute myeloid leukaemia domain protein 1, gene map locus 5q35, associated with t(11;17)(q13;q21) encodes a widely expressed SET domain NUP98 a gene, Nucleoporin 98, gene map protein; two transcripts are made from locus 11p15; encodes a component of the the gene, one of which is only seen in nuclear pore complex which regulates haemopoietic cells; NSD1 contributes to nucleocytoplasmic transport of protein NUP-NSD1 and NSD1-NUP98 fusion and RNA; belongs to a subgroup of nucleo- genes in childhood acute myeloid leuk- porins that contain FG (phenylalanine- aemia associated with t(5;11)(q35;p15.5) glycine) repeats which are docking sites nuclear magnetic resonance imaging for nuclear transport receptors; NUP98 (NMR) see magnetic resonance imaging contributes to: (MRI) • the NUP98-PMX1 fusion gene in nuclear membrane the lipid bilayer therapy-related acute myeloid leukaemia that encloses the nucleus and blast crisis of chronic granulocytic nucleated red blood cell (NRBC) the leukaemia associated with t(1;11)(q23;p15) term often used to designate erythroblasts • the NUP98-HOXD13 gene and the in the circulating blood NUP-FN1 gene in therapy-related and de nucleolus a unique region of the nucleus novo acute myeloid leukaemia associated created by the transcription of rRNA with t(2;11)(q31;p15) nucleoside a purine or pyrimidine base • the NUP98-RAP1GDS1 gene in T- bonded to a pentose sugar (see also lineage acute lymphoblastic leukaemia nucleotide) associated with t(4;11)(q21;p15) nucleoside analogue drugs which • the NUP-NSD1 and NSD1-NUP98 are analogues of nucleosides, including fusion genes in childhood acute myeloid a group of anti-cancer drugs (ﬂudara- leukaemia associated with bine, pentostatin and cladribine) and t(5;11)(q35;p15.5) also certain drugs used in treating HIV • the NUP98-HOXA9 fusion gene in infection myelodysplastic syndrome and acute nucleotide the basic unit of DNA and myeloid leukaemia associated with RNA: a nucleotide is composed of a t(7;11)(p15;p15) HAE-N 01/13/2005 05:14PM Page 174

174 NUP214

• the NUP98-HOXA11 fusion gene in a and therapy-related acute myeloid leuk- patient with Ph-negative chronic myeloid aemia and myelodysplastic syndromes leukaemia progressing rapidly to acute • the NUP98-TOP1 gene in therapy- myeloid leukaemia related acute myeloid leukaemia or • the NUP98-FGFR1 fusion gene in myelodysplastic syndrome associated acute myeloid leukaemia associated with with t(11;20)(p15;q11) t(8;11)(p11;p15) In all cases, chimaeric proteins involving • a fusion gene with LEDGF in a patient NUP98 carry the amino terminal FG with de novo acute myeloid leukaemia repeats of NUP98 fused to the carboxy associated with t(9;11)(p22;p15) terminus of the partner protein; the FG • the NUP98-DDX10 gene in repeats enable inv(11)(p15q22) associated with de novo NUP214 see CAN HAE-O 01/13/2005 05:14PM Page 175

O2 oxygen oncogene a transduced, cancer-inducing oat cell carcinoma a previous designa- gene in the genome of a transforming tion of small cell carcinoma of the lung virus; most oncogenes have cellular coun- occult hidden, as in ‘occult neoplasm’ terparts, termed proto-oncogenes which Oct2 a transcription factor for immuno- have normal physiological functions, but globulin genes which is expressed in the which may be either dysregulated or neoplastic cells of nodular lymphocyte structurally modified and contribute to predominant Hodgkin’s disease but oncogenesis in various tumours; the term not in the neoplastic cells of classical ‘oncogene’ is often used to refer not only Hodgkin’s disease to these proto-oncogenes but also to any oedema an increase of interstitial (or gene that contributes to the development, intra-alveolar) fluid maintenance or further evolution of a OK a blood group system, antigens being neoplastic condition encoded by polymorphic variants of the oncogenesis the process of develop- BSG gene at 19p13.3 ment of a tumour or other neoplasm oligoclonal a description of lympho- oncoprotein a protein encoded by an cytes, plasma cell or both belonging to a proto-oncogene that causes or contributes small number of clones to the malignant phenotype of a neo- oligonucleotide a short chemically plastic cell produced sequence of nucleotides, often open reading frame a series of triplet complementary to a sequence of cellular codes that can be read as a genetic message DNA or RNA and therefore suitable for ophthalmic pertaining to the eye use as a probe or as a PCR primer ophthalmology the branch of medicine oliguria marked reduction in urine dealing with the eye production ophthalmoscope a device for examin- Omenn’s syndrome combined immun- ing the interior of the eye odeficiency with absence of circulating opportunistic infection an infection B cells and presence of activated oligo- that occurs as a result of reduced host clonal T cells, which infiltrate the skin defences, e.g. in a patient with a lympho- and intestine, resulting from a mutation proliferative disorder or AIDS or dur- of the RAG1 or RAG2 genes; clinical ing the administration of anti-cancer features often include erythroderma, chemotherapy, often caused by an organ- lymphadenopathy, hepatomegaly, spleno- ism that in the normal host is generally megaly and an increased incidence of non-pathogenic life-threatening infections. opsonin a protein, such as immunoglo- OMIM Online Mendelian Inheritance in bulin or an activated complement compon- Man, website http://www.ncbi.nlm.nih. ent, that coats a foreign particle, such as gov/omim/ a bacterium, and by so doing makes onchocerciasis a disease resulting from phagocytosis more likely infection by the parasite Onchocerca opsonization the binding of an opsonin volvulus to a bacterium or other foreign particle

175 HAE-O 01/13/2005 05:14PM Page 176

176 optic

optic pertaining to vision Figure 57 An osmotic fragility curve. optic atrophy atrophy of the optic An osmotic fragility curve showing that erythrocytes nerve, the end stage of optic neuropathy, from a patient with hereditary spherocytosis lyse may be a feature of vitamin B deﬁciency more readily than normal cells in a hypo-osmolar 12 solution. optic disc the pale area at the back of the eye where the optic nerve enters the eye 100 optic nerve one of the two cranial nerves arising in the retina and conducting 80 impulses to the optic cortex of the brain 60 optic neuropathy degeneration of the neurones of the optic nerve, may be a 40

feature of vitamin B12 deﬁciency

Haemolysis (%) 20 oral pertaining to the mouth Oraya fever a disease occurring in 0 South America, resulting from infection 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 by Bartonella bacilliformis and having Sodium chloride (%) haemolytic anaemia as one of its features organ an arrangement of tissues into a compact organized structure with specific functions osteitis fibrosa cystica a disorder of organelle one of a group of highly organ- bone resulting from a combination of ized membrane-enclosed structures within hyperparathyroidism and osteomalacia the cytoplasm, each with its own specific osteoarthritis a degenerative rather function, e.g. mitochondrion, Golgi appar- than inflammatory arthritis atus, endoplasmic reticulum, lysosome, osteoblast a bone-forming cell of mes- peroxisome enchymal but not haemopoietic origin organic pertaining to substances con- osteoclast a generally multinucleate bone- taining carbon from living or once living destroying cell of monocyte lineage sources osteocyte a bone cell found in small organism a living animal or plant or any cavities within bone, derived from an size from a microbe to man osteoblast that has been enclosed in bone organomegaly enlargement of organs; osteogenesis imperfecta an inherited in haematological jargon ‘no organ- disorder of bone resulting from a defect omegaly’ usually indicates no enlarge- in collagen synthesis and leading to thin- ment of the abdominal organs such as the ning of the cortex and bony trabeculae liver and spleen osteoid non-calcified bone osmolarity a measure of the concentra- osteomalacia a disorder of bone, result- tion of solutes in a solution ing from vitamin D deficiency, in which osmosis the movement of a solvent such there is defective mineralization as water through a semipermeable mem- osteomyelitis infection of bone brane from a less to a more concentrated osteomyelosclerosis an advanced solution stage of idiopathic myelofibrosis in which osmotic fragility curve a graphical there is osteosclerosis as well as bone representation of the results of an osmotic marrow fibrosis fragility test (Fig. 57) osteopetrosis marble bone disease, a osmotic fragility test a test of the resis- congenital form of osteosclerosis, result- tance of red cells suspended in hypotonic ing from a defect in osteoclast numbers solutions to lysis or function, which leads to bone marrow osmotic pressure the pressure exerted failure on a semipermeable membrane by a solu- osteoporosis a reduction of bone den- tion containing solutes that cannot cross sity due to thinning of the cortex and the membrane medullary trabeculae HAE-O 01/13/2005 05:14PM Page 177

oxyhaemoglobin 177

osteosclerosis thickening of bony the need to change to alternative treat- trabeculae ment (see also disease-free survival, event- OTT a gene, One Twenty Two, gene map free survival) locus 1p12, also known as RNA-Binding overt obvious, readily apparent Motif protein 15, RBM15; encodes a ovum (plural ova) a germ cell produced ribonucleoprotein; OTT is a homologue in the ovary of a female of the Drosophila gene spen (split ends); oxalosis an inherited metabolic disorder its function in man is unclear; OTT con- leading to deposition of oxalic acid crys- tributes to the OTT-MAL fusion gene tals in tissues including the bone marrow (also known as RBM15-MKL1 fusion oximeter a device or instrument for gene ) in infant M7 acute myeloid leuk- measuring the oxygen saturation of blood aemia associated with t(1;22)(p13;q13) oxygen (O2) a tasteless, colourless gas (see also RBM15 and MKL1) that is essential for metabolism and there- ovalocyte an oval red cell fore for life; transferred to the blood ovalocytosis an inherited abnormality stream from the inspired air in the alveoli of the erythrocyte membrane in which of the lungs and transported to tissues by cells are oval in shape haemoglobin overall survival survival, regardless of oxyhaemoglobin haemoglobin com-

whether there has been disease relapse or bined with O2 HAE-P 01/13/2005 05:14PM Page 178

3 prime (3′) the end of a gene where 9p21 in tandem with INK4b (see also transcription terminates Table 5, p. 70) 5 prime (5′) the end of a gene where p18 the protein encoded by CDKN2C transcription commences p19 the protein encoded by CDKN2D 8p11 syndrome a myeloproliferative/ p21RAS the product of the RAS gene lymphoproliferative stem cell disorder p21WAF a protein that negatively regu- resulting from one of a number of lates cell proliferation, encoded by the translocations that involved the FGFR1 CDKN1A gene gene, characterized by a myeloproliferat- p27 the protein encoded by CDKN1B ive disorder with eosinophilia, T-lineage p51 a homologue of p53 lymphoblastic lymphoma and evolution p50 the partial pressure of oxygen at to acute myeloid leukaemia which haemoglobin is half saturated 32P a radio-active isotope of phosphorus, p53 a 53 kD protein encoded by the used in the treatment of myeloprolifer- tumour suppressor gene TP53; p53 is ative disorders a transcription factor that upregulates p (i) the short arm of a chromosome, from CDKN1A (encoding p21Cip1/ Waf1) and the French petit (ii) an abbreviation for therefore arrests the cell cycle temporar- protein, e.g. p53, the protein encoded by ily at G1/S, thus allowing time for detec- the TP53 tumour suppressor gene tion and repair of damaged DNA; in p+ a chromosome with material added to addition, p53 increases BAX expression, the short arm thus promoting apoptosis of damaged cells p− a chromosome with loss of material p57 the protein encoded by CDKN1C from the short arm p73 a homologue of p53 P a blood group system with the great p300 the provisional name for a gene,

majority of individuals expressing the P1 E1A-binding protein, 300-kD; gene map antigen; P1-negative (p) individuals are locus 22q13; encodes a bromodomain con- resistant to parvovirus B19 infection; the taining transcriptional adaptor protein

P1 antigen is an indirect, carbohydrate- which is very similar in function to CBP; deﬁned product of the P gene at 22q11.2- contributes to: qter; autoanti-P is a biphasic haemolysin • the MLL-p300 fusion gene in acute causing paroxysmal cold haemoglobinuria myeloid leukaemia associated with p15 a protein that negatively regulates t(11;22)(q23;q13); cell proliferation by inhibiting cyclin– • contributes to the MOZ-p300 and cyclin-dependent kinase 4 complexes, p300-MOZ fusion genes in M5 acute encoded by the CDKN2B gene (also myeloid leukaemia associated with known as INK4b) at 9p21 (see also Table t(8;22)(p11;q13) 5, p. 70) packed cell volume (PCV) the propor- p16 a protein that negatively regulates tion of a column of centrifuged anti- cell proliferation, encoded by the coagulated blood which is occupied by CDKN2A gene (also known as INK4a, erythrocytes or an equivalent measurement MTS1 and CDKN2) which is located at determined by an automated instrument

178 HAE-P 01/13/2005 05:14PM Page 179

partial remission (PR) 179

‘packed film’ jargon for a thick blood paracrine a hormonal pathway charac- film, characteristic of polycythaemia terized by the production of a biologically ‘packed marrow’ jargon for a heavy active substance that passes by diffusion to uniform infiltration of the bone marrow a nearby cell where it initiates a response by neoplastic, usually lymphoma, cells paraprotein an abnormal monoclonal PAFAH2 a gene, Platelet-Activating immunoglobulin produced by a neoplas- Factor Acetylhydrolase 2, gene map locus tic clone of cells, either a complete 11q23, encodes a widely expressed cyto- immunoglobulin molecule or a mono- plasmic protein; dysregulated by proxim- clonal heavy chain or light chain ity to the IGH locus in t(11;14)(q23;q32) parasitaemia the presence of parasites associated with B-cell malignancy in the blood Paget’s disease, Paget’s disease of parasite an organism which lives in or on bone an acquired disorder of bone another creature, causing some damage in which the normal lamellar pattern to its host of mature bone is lost, the bone show- parasthesiae abnormal sensations such ing a mosaic pattern in histological as tingling, numbness, ‘pins and needles’; sections can be indicative of peripheral neuropathy

PAI-1 plasminogen activator inhibitor 1 and be a feature of vitamin B12 deficiency PAI-2 plasminogen activator inhibitor 2 or caused by chemotherapy with vinca paired box a DNA-binding domain pre- alkaloids sent in a family of transcription factors paratrabecular adjacent to a bony (PAX proteins); several members of this spicule, characteristic site of bone mar- family also contain homeodomains row infiltration in follicular lymphoma palliative treatment treatment in- parietal cell a stomach cell secreting tended to relieve symptoms hydrochloric acid and intrinsic factor pallidin a red cell membrane protein, parietal cell antibodies autoantibod- previously known as band 4.2, encoded ies directed at parietal cells, a feature of by the EPB42 gene at 15q15 (see Fig. 64, pernicious anaemia (present in 90–95% of p. 199) patients) and atrophic gastritis (present pancreas an abdominal organ with both in 60% of patients) but also present not endocrine and exocrine functions, secret- infrequently in apparently healthy elderly ing insulin and digestive enzymes people pancreatitis inflammation of the paroxysmal cold haemoglobinuria pancreas (PCH) an acquired haemolytic anaemia pancytopenia reduction in the white characterized by biphasic antibody- cell count, the red cell count (and mediated haemolysis; an antibody, haemoglobin concentration) and the usually anti-P, designated a Donath– platelet count Landsteiner antibody, is bound to the cell PaO2 partial pressure of oxygen in arterial in the cold and with rewarming there is blood complement-induced lysis papilloedema swelling of the optic disc paroxysmal nocturnal haemoglobin- Pappenheimer bodies iron-containing uria (PNH) an acquired haemolytic inclusions in erythrocytes, as seen on a anaemia characterized by intermittent Romanowsky stain haemolysis, and often pancytopenia, con- papule a small raised skin lesion sequent on a clonal genetic disorder with paracentric a term to describe a chro- a mutation in a PIG-A gene mosomal inversion which involves the partial pressure of oxygen that part long arm or the short arm but not both of the total blood gas pressure exerted by paracortex adjacent to the cortex, e.g. oxygen the part of a lymph node immediately partial remission (PR) regression of a below the cortex, occupied mainly by T disease but with clinical or pathological lymphocytes evidence of residual disease HAE-P 01/13/2005 05:14PM Page 180

180 partial thromboplastin time

partial thromboplastin time the time • is dysregulated by proximity to the for clotting to occur if a partial thrombo- IGH enhancer in t(9;14)(p13;q32) found plastin, acting as a platelet substitute in in about 50% of cases of lymphoplasma- the intrinsic pathway of coagulation, is cytoid lymphoma added to plasma (see also activated partial • was dysregulated by replacement thromboplastin time) which has now of its promoter by the IGH switch Sµ replaced the (non-activated) partial promoter in a splenic marginal zone thromboplastin time lymphoma associated with parvovirus B19 a very small double- t(2;9;14)(p12;p13;q32) stranded DNA virus which is the cause • is dysregulated by proximity to IGH in of erythema infectiosum or fifth disease; t(9;14)(p13;q32) in B-cell non-Hodgkin’s parvovirus is capable of causing pure red lymphoma cell aplasia (with anaemia generally • contributed to a PAX5-ETV6/TEL occurring only when the red cell survival fusion gene in a case of acute lymphoblas- is shortened) and, less often, neutropenia tic leukaemia or thrombocytopenia; infection during PAX7 a gene, Paired box gene 7, also pregnancy can lead to severe fetal known as HUP1, gene map locus 1p36.2, anaemia and hydrops fetalis encodes a paired box transcription factor PAS periodic acid-Schiff stain which also has a homeodomain; con- pathogen a micro-organism capable of tributes to the PAX7-FKHR fusion causing disease gene, in t(1;13)(p36;q14) associated with pathogenesis the process by which a alveolar rhabdomyosarcoma disease develops PB peripheral blood pathogenic capable of causing disease PBSCT peripheral blood stem cell trans- pathognomonic an abnormality which plantation is diagnostic of a certain condition, i.e. PBX1 a gene, Pre-B-cell leukaemia tran- that permits no other diagnosis scription factor 1, gene map locus 1q23, pathology the study of disease encodes a ubiquitously expressed non- Paul–Bunnell test a test for the cluster (class II) homeobox transcription heterophile antibody characteristic of factor; archetypal member of a family of infectious mononucleosis homeobox genes that modulate the activ- Pautrier’s abscess or microabscess a ity of other homeobox genes by forming focal accumulation of T lymphocytes heterodimeric complexes with them, the within the epidermis, a feature of cuta- complexes having high binding activity neous T-cell lymphoma on a subset of potential DNA recognition PAX3 Paired box gene 3, gene map sites; these complexes can be inhibitory locus 2q35, encodes a paired box tran- or activating; PBX1 contributes to the scription factor which also has a homeo- E2A-PBX1 fusion gene in B-lineage acute domain; germline mutations in this gene lymphoblastic leukaemia associated with are seen in the dysmorphic disorder t(1;19)(q23;p13) Waardenburg’s syndrome type I; PAX3 PcAb polyclonal antibody contributes to the fusion gene, PAX3- PCH paroxysmal cold haemoglobinuria FKHR, in t(2;13)(q35)(q14) associated PCR polymerase chain reaction with alveolar rhabdomyosarcoma PCR-SSOP polymerase chain reaction– PAX5 a gene, Paired box gene 5, gene sequence-specific oligonucleotide probing map locus 9p13, also known as B-cell PCR-SSP polymerase chain reaction– lineage-Specific Activator Protein, BSAP; sequence-specific priming gene map locus 9p13, encodes a paired PCV packed cell volume box transcription factor expressed at PDGFRB a gene, Platelet-Derived early stages of B-cell differentiation, but Growth Factor Receptor Beta, gene which also regulates isotype switching; map locus 5q33, encodes the beta chain PAX5: of the PDGF receptor β, also known HAE-P 01/13/2005 05:14PM Page 181

periodic acid-Schiff stain (PAS stain) 181

as CD140b, a dimeric receptor tyrosine Figure 58 Pelger–Huët anomaly. kinase, at 5q33 which contributes to: A diagram contrasting a normal segmented • the ETV6-PDGFRB fusion gene in neutrophil and band form with two neutrophils chronic myelomonocytic leukaemia showing the Pelger–Huët anomaly. with eosinophilia associated with t(5;12)(q33;p13); • the H4(10S170)-PDGFRB gene in atypical chronic myeloid leukaemia associated with t(5;10)(q33;q22); • the HIP1-PDGFRB fusion gene in chronic myelomonocytic leukaemia Normal neutrophil associated with t(5;7)(q33;q11.2); and neutrophil • Rabaptin5-PDGFRB fusion gene in a band form patient with CMML in each case, the fusion protein encodes a constitutively activated tyrosine kinase receptor Pearson’s syndrome a mitochondrial cytopathy, resulting from deletion of mitochondrial DNA, characterized haematologically by neutropenia, sidero- Neutrophils in .. blastic erythropoiesis and vacuolation of Pelger–Huet anomaly haemopoietic cells; non-haematological manifestation may include exocrine pancreatic deficiency, metabolic acidosis, renal disease, liver failure and diabetes mellitus peptic ulceration ulceration of the pegylation attachment of a polyeth- stomach or duodenum induced by gastric lyene glycol (PEG) polymer group to a secretions protein, such as thrombopoietin, inter- percentile one hundredth part of a feron or granulocyte colony-stimulating statistical distribution; a conventional factor, in order to decrease plasma clear- 95% reference range extends between the ance and increase efficacy 2.5 and the 97.5 percentiles Pel–Ebstein fever a periodic fever, PERF1 the gene, Perforin, gene map locus characteristic of Hodgkin’s disease 10q22, encoding perforin; germ-line Pelger–Huët anomaly an inherited mutation in this gene is the cause of famil- anomaly in which neutrophils are ial haemophagocytic lymphohistiocytosis hypolobulated but functionally normal type 2 (Fig. 58) perforin a protein secreted by cytotoxic pencil cell a particularly long thin ellip- T cells and NK cells that is inserted into tocyte, typical of iron deficiency anaemia the membrane of a target cell, creating a but not pathognomonic pore through which cytotoxic enzymes, penetrance the expression of a gene, a granzymes, can enter with resultant gene either being expressed or not activation of caspases and apoptosis penicilliosis infection by fungi of the pericentric a term to describe a chromo- genus Penicillium, e.g. by Penicillium somal inversion that has breakpoints on marneffei either side of the centromere so that the pentose shunt a metabolic pathway centromeric parts of both long and short which gives cells the ability to resist arms are involved in the inversion oxidant damage (Fig. 59) periodic acid-Schiff stain (PAS stain) pentostatin a nucleoside analogue used a cytochemical stain for complex carbo- in treating hairy cell leukaemia hydrates including glycogen HAE-P 01/13/2005 05:14PM Page 182

182 periosteum

Figure 59 The pentose shunt. A diagram showing the pentose shunt and related metabolic pathways.

γ -glutamylcystelne synthetase ROOH ROH + H2O and Glutathione synthetase Glutathione peroxidase

Reduced Glutathione glutathione (GSSG) (GSH) Glutathione reductase Haemoglobin

Glucose NADP NADPH Methaemoglobin reductase ATP Hexokinase NADP ADP Methaemoglobin

Glucose-6-phosphate 6-phosphogluconoδ lactone Glucose-6-phosphate dehydrogenase 6-phosphoglucono- Glucosephosphate lactonase isomerase Pentose shunt Fructose-6-phosphate 6-phosphogluconate

ATP NADP 6-phosphogluconate Phosphofructokinase dehydrogenase ADP NADPH Glycolytic pathway

Fructose-1,6 diphosphate Ribulose-5-phosphate

Aldolase Ribulose-5-phosphate isomerase

Transketolase Glyceraldehyde 3-phosphate Ribose-5-phosphate

periosteum the connective tissue cells peripheral T-cell lymphoma all T- covering the surface of a bone lineage lymphomas except those com- peripheral blood (PB) the blood cir- posed of lymphoblasts culating through arteries and veins peripheral vascular disease narrow- peripheral blood stem cell transplan- ing of the arteries to the limbs, usually tation (PBSCT) transplantation of caused by atheroma haemopoietic stem cells harvested from Perls’ stain a Prussian blue stain, used to the peripheral blood identify iron in the form of haemosiderin peripheral neuropathy degeneration permeabilization the process by which of the peripheral nerves, may be caused a cell is made permeable to antibodies so

by vitamin B12 deﬁciency or be associated that intracellular antigens can be recognized with the presence of a paraprotein pernicious injurious, destructive, fatal HAE-P 01/13/2005 05:14PM Page 183

PKB 183

pernicious anaemia an autoimmune phagosome the cytoplasmic vacuole disease characterized by gastric atrophy, that results from phagocytosis inadequate gastric secretion of intrinsic pharyngitis inﬂammation of the pharynx

factor, vitamin B12 deﬁciency and mega- pharynx the throat loblastic anaemia; other features may phenotype the appearance of some- include peripheral neuropathy, optic atro- thing, cf. genotype phy and subacute combined degeneration Philadelphia chromosome (Ph chro- of the spinal cord; pernicious anaemia is mosome) a 22q– chromosome formed part of a spectrum of autoimmune dis- as a result of t(9;22)(q34;q11) eases that includes diabetes mellitus, auto- phlebotomy removal of blood from a vein immune thyroid disease and vitiligo; since for therapeutic or diagnostic purposes

vitamin B12 became available for treatment phosphofructokinase an erythrocyte this anaemia is no longer ‘pernicious’ enzyme in the glycolytic pathway (see peroxisomes organelles containing Fig. 33, p. 113) oxidative enzymes and responsible for phosphoglyceratekinase an erythro- detoxification cyte enzyme in the glycolytic pathway pertussis whooping cough, the illness (see Fig. 33, p. 113) resulting from Bordetella pertussis infec- phosphoinositides (PIs) phospha- tion; the major haematological feature is tidylinositol phospholipids, a group of lymphocytosis lipid second messenger molecules PET pre-eclamptic toxaemia phototherapy a method of treating petechiae pin-point skin haemorrhages, neonatal hyperbilirubinaemia by exposure a form of purpura of the baby to ultraviolet light PET scan positron emission tomography Phox homology (PX) domain a phos- scan phoinositide (PI)-binding protein motif Peyer’s patches a focal accumulation of which plays a critical role in the intracel- lymphocytes in the small intestine, part lular localization of a variety of cell- of the mucosa-associated lymphoid tissue signalling proteins (MALT) phytohaemagglutinin a plant lectin able PFGE pulsed field gel electrophoresis to stimulate T lymphocyte to proliferate pH an abbreviation of ‘potential hydro- pica a craving to eat unusual substances, gen’, an expression of the H+ ion concen- e.g. ice or clay; can be a feature of iron tration; water has a pH of 7.0 and is deficiency considered chemically neutral; acids have Pickwickian syndrome polycythaemia a pH below 7.0 and alkalis a pH above consequent on hypoventilation and 7.0 hypoxia in severe obesity Ph the Philadelphia chromosome; it picogram 1 × 10–12 of a gram should be noted that the preferred abbre- PIFT platelet immunofluorescence test viation is now Ph not Ph1 PIG-A a gene at Xp22.1 (glycosylphos- phagocyte a cell capable of ingesting and phatidylinositol-glycan complementa- destroying micro-organisms and cellular tion class A), encoding one of the four debris, e.g. a neutrophil or a macrophage genes necessary for synthesis of glyco- phagocytic pertaining to phagocytosis, sylphosphatidylinositol (GPI); mutated in able to carry out phagocytosis paroxysmal nocturnal haemoglobinuria phagocytosis the ingestion of a cell or PIK3CA a gene, Phosphatidylinositol-3 inert material by a phagocytic cell such as Kinase p110 Catalytic Alpha subunit, a neutrophil or monocyte; a specialized gene map locus 3q26-27, encodes the form of endocytosis catalytic subunit of phosphatidylinositol- phagolysosome the cytoplasmic vac- 3 kinase, that is amplified and over- uole that results from fusion of a phago- expressed in several gynaecological some with the cytoplasmic granules of a malignancies neutrophil or monocyte PKB see AKT1 HAE-P 01/13/2005 05:14PM Page 184

184 PKLR

PKLR a gene at 1q21 encoding liver and deficiency, which is very rare, is associ- red cell pyruvate kinase; mutation may ated with increased risk of thrombosis lead to pyruvate kinase deficiency and plasminogen activator a serine pro- consequent chronic haemolytic anaemia tease, synthesized by vascular endothelial plaque a skin lesion that is elevated but cells, that activates plasminogen; defici- flat ency, which is very rare, is associated with plasma the fluid part of blood; plasma an increased risk of thrombosis for laboratory tests is prevented from plasminogen activator inhibitor 1 clotting by the addition of either an (PAI-1) a serpin, a plasma protein that anticoagulant or a chelating agent that inhibits plasminogen activator; mutations binds calcium of the gene, which are very rare, can lead plasma cell the end cell of the B- to increased levels, which are associated lymphocyte lineage; an antibody-secreting with an increased risk of thrombosis cell plasminogen activator inhibitor 2 plasma cell dyscrasia any plasma cell (PAI-2) a serpin, an intracellular and neoplasm, including multiple myeloma, extracellular inhibitor of plasminogen monoclonal gammopathy of undeter- activator, expressed in monocytes, mined significance, light-chain-associated endothelial cells and other cells amyloidosis platelet a fragment of megakaryocyte plasma cell leukaemia a leukaemia of cytoplasm which circulates in the blood cells analogous to normal plasma cells, and participates in haemostasis occurring either de novo or as the terminal platelet glycoprotein (Gp) surface phase of multiple myeloma membrane antigen of platelets but may plasmacytoma a tumour composed of also be expressed on other cells neoplastic plasma cells platelet glycoprotein Ia/IIa (GpIa/IIa) plasmacytosis increased numbers of a platelet glycoprotein that mediates plasma cells in the blood or bone marrow collagen adhesion; carries HPA-5 and plasma membrane the lipid bilayer HPA-13w antigens which encloses a cell platelet glycoprotein Ib/IX/V (Gp plasmapheresis removal of plasma Ib/IX/V) a platelet glycoprotein that from the circulating blood by connection binds von Willebrand’s factor and medi- of the patient’s blood stream to a special- ates adhesion to damaged endothelium; ized centrifuge, usually performed as part there is lack of expression in Bernard– of plasma exchange therapy but occa- Soulier syndrome; GpIbα carries HPA-2 sionally used to obtain plasma for trans- antigens and GpIbβ carries HPA-12w fusion; the plasma removed is replaced by antigens (see Table 9, p. 131) an isotonic solution platelet glycoprotein IIb/IIIa (Gp plasma protein the proteins in plasma, IIb/IIIa) a platelet glycoprotein that classified according to their electrophor- binds fibrinogen, fibronectin and vit- etic mobilities and chemical character- ronectin and has an important role in istics as albumin, α, β and γ globulins platelet aggregation; there is lack of and fibrinogen expression in Glanzmann’s thrombasthe- plasma volume the total volume nia; GpIIb carries HPA-3 and HPA-9w of plasma in the circulating blood, antigens; GpIIIa caries HPA-1, HPA-4, can be measured by isotopic dilution HPA-6, HPA-7w, HPA-8w, HPA-10w and techniques HPA-11w antigens (see Table 9, p. 131) plasmid a circular autonomously replic- platelet glycoprotein IV CD36, carries ating extrachromosomal DNA molecule the Vis antigen which has not yet been plasmin an specific enzyme capable of assigned an HPA number degrading fibrin (see Fig. 27, p. 103) platelet glycoprotein VI a platelet gly- plasminogen a plasma protein that is coprotein required for collagen-induced converted to plasmin (see Fig. 27, p. 103); aggregation HAE-P 01/13/2005 05:14PM Page 185

POD 185

platelet immunofluorescence test locus11q23.1, that encodes a zinc finger (PIFT) a test for anti-platelet antibodies transcriptional repressor of the BTB/ platelet peroxidase the isoenzyme of POZ family, normally expressed in prim- peroxidase that is present in megakary- itive haemopoietic cells; transcriptional ocytes and platelets repression is mediated via the amino ter- plateletpheresis removal of platelets minal POZ domain; PLZF contributes form the circulating blood, usually to to the PLZF-RARA fusion gene in obtain platelets for transfusion but occa- t(11;17)(q23;q21) associated with M3- sionally to remove platelets from a like acute myeloid leukaemia patient with thrombocytosis PML nuclear body (POD) a multipro- platelet-poor plasma plasma from tein nuclear organelle where transcriptional which the majority of platelets have been regulatory proteins are assembled and removed by centrifugation, used for modified in response to cellular signals; coagulation tests POD structure and function is disrupted platelet-rich plasma plasma from in acute promyelocytic leukaemia which platelets have not been removed, PML a gene, Promyelocytic Leukaemia; used for platelet aggregation studies gene map locus 15q22, encodes a RING platelet-type von Willebrand’s dis- finger protein which is a component of ease an autosomal dominant form of multiprotein nuclear organelles known von Willebrand’s disease in which a gain- as PML nuclear bodies or PODs; PODs of-function mutation of GPIBA, the gene are structures where transcriptional encoding platelet glycoprotein Ib, leads regulatory proteins are assembled and to increased binding of von Willebrand modified in response to cellular signals; factor by platelets, platelet aggregation, PML complexed in PODs can act as a thrombocytopenia and reduced con- transcriptional repressor or activator; centration of plasma von Willebrand’s contributes to a PML-RARA fusion factor gene in t(15;17)(q22;q21) associated with pleckstrin homology (PH) domain a M3 and M3 variant acute myeloid leuk- phosphoinositide (PI)-binding protein aemia (acute promyelocytic leukaemia); motif involved in intracellular signalling, in M3 AML, PML is dispersed from cytoskeletal organization and regulation PODs into hundreds of tiny structures of intracellular membrane transport throughout the cytoplasm and nucleus pleomorphic varying considerably in (microparticulate pattern); normal PODs size, shape and other characteristics reappear on treatment with all-trans- pleomorphism showing considerable retinoic acid; PML-RARA exerts a domin- variation on size, shape and other ant negative effect on wild type RARα characteristics function pleura the thin layer of cells covering PMX1 a gene, Paired Mesoderm the surface of the lungs and the internal Homeobox, also known as PHOX1, gene surface of the thoracic cage map locus 1q23, encodes a non-cluster pleural effusion the accumulation of (class II) homeobox protein expressed in fluid in the pleural space cardiac, skeletal, and smooth muscle tis- Plummer–Vinson syndrome oesopha- sues in adults; contributes to the NUP98- geal webs associated with iron deficiency PMX1 fusion gene in acute myeloid anaemia leukaemia and blast crisis of chronic pluripotent stem cell a stem cell granulocytic leukaemia associated with capable of giving rise to both lymphoid t(1;11)(q23;p15); the fusion protein local- and myeloid lineages, the common izes to the nucleus and may function as a lymphoid–myeloid progenitor cell transcription factor PLZF a gene, Promyelocytic Leukaemia PNH paroxysmal nocturnal haemoglobinuria Zinc Finger gene, also known as Zinc Po2 partial pressure of oxygen Finger protein 145, ZNF145, gene map POD PML nuclear body HAE-P 01/13/2005 05:14PM Page 186

186 POEMS syndrome

POEMS syndrome a syndrome polymerase chain reaction (PCR) an resulting from a plasma cell neoplasm enzymatic method for the exponential and characterized by Polyneuropathy, amplification of target DNA in vitro Organomegaly (hepatomegaly, spleno- using a thermostable DNA-dependent megaly, lymphadenopathy), Endocrino- DNA polymerase, target-specific oligonu- pathy, M-protein and Skin changes cleotide primers and cyclical reaction poikilocyte an erythrocyte of abnormal conditions that allow the repeated denat- shape uration of nascent products (double- poikilocytosis the presence of poikilo- stranded DNA being converted to cytes in the blood; increased variability single-stranded DNA) and re-annealing in the shape of erythrocytes of primers (Fig. 60) point mutation the substitution of a polymerase chain reaction– single base in a DNA molecule that may sequence-specific oligonucleotide result in (i) no change in the amino acid probing (PCR-SSOP) a PCR tech- encoded (ii) encoding of a different nique using generic primers that will amino acid (iii) conversion of a coding amplify all alleles of interest followed by codon to a stop codon (iv) conversion of the application of probes specific for each a stop codon to a coding codon (v) inter- allele, used for HLA typing ference with splicing polymerase chain reaction– polyarteritis nodosa an inflammatory sequence-specific priming (PCR- disorder of blood vessels SSP) a PCR technique using primers polychromasia the presence of a blue that will amplify only a specific allele, tinge in the cytoplasm of erythrocytes, used for HLA and HPA typing indicative of a young red cell polymerization formation of a polychromatic cell an erythrocyte with polymer, e.g. the polymerization of a blue tinge to the cytoplasm, indicating haemoglobin S at low oxygen tensions that it is a young red cell polymorph jargon for a neutrophil polychromatic macrocyte a poly- polymorphism the presence in a popu- chromatic cell that is larger than normal lation of two variants of a gene so that erythrocytes the frequency of the least common is polyclonal a description of lympho- at least 1%, e.g. βS is polymorphic in cytes, plasma cells or both belonging to West African populations many clones polymorphonuclear leucocyte polyclonal antibody (PcAb) an anti- strictly any granulocyte but the term is body derived from polyclonal lympho- more often applied only to neutrophil cytes, e.g. produced by immunization of granulocytes an animal, also known as an antiserum polymyalgia rheumatica an inflam- polyclonal gammopathy an increased matory condition of muscles with a concentration of polyclonal immuno- characteristically high erythrocyte sedi- globulins mentation rate polycythaemia an increased red cell polypeptide a chain of amino acids count, haemoglobin concentration and linked by peptide bonds packed cell volume polyploid having multiple sets of chro- polycythaemia rubra vera a myelo- mosomes, e.g. normal megakaryocytes proliferative disorder mainly affecting are polyploid as are some neoplastic cells erythropoiesis; the WHO classification porphyria a disease resulting from abnor- prefers the designation ‘polycythaemia mal tissue accumulation of porphyrins vera’ porphyria cutanea tarda an inherited polycythaemia vera see polycythaemia or acquired condition characterized by rubra vera skin fragility and formation of bullae in polymer a compound formed by the link- sun-exposed areas; familial cases may ing together of like or unlike monomers result from mutation in the URO-D gene, HAE-P 01/13/2005 05:14PM Page 187

porphyria cutanea tarda 187

Figure 60 The polymerase chain reaction (PCR). The first four rounds of a polymerase chain reaction (PCR) are shown. The reaction mixture contains template, oligonucleotide DNA primers specific for the target sequence to be amplified, reaction buffer and a thermostable DNA polymerase enzyme. The starting template (either double stranded DNA or a DNA/RNA hybrid [reverse- transcription PCR]) is heat denatured and allowed to cool so that the first oligonucleotide can bind to (anneal to) its target sequence; it is then warmed to the optimum temperature for polymerase activity; the thermostable polymerase generates nascent DNA complementary to the sequence 3′ to the primer. Subsequent denaturation and annealing allows for further polymerization, this time nascent DNA can also act as a template. The initial products are heterogeneous in size but eventually a product of a size defined by the distance between the primers will predominate.

Either Or 3' 5'3' 5' 5' 3' 5' 3' Double stranded Reverse transcribed (genomic) DNA cDNA

Heat denaturation

5' 3' Single stranded DNA template 5' Leftward primer annealing

Primer extension First cycle 5' 3' Primer extension 5' catalysed by thermostable DNA Heat polymerase denaturation

5' 3' 5' Single stranded DNA templates 5' 5' Leftward and rightward primer annealing Second Primer extension cycle 5' 3' 5' 5' 5'

5' 3' 5' 5' 5' Third 5' 5' 5' 5' cycle

5' 5' 5' 5' 5' 5' 5' 5' Fourth 5' 3' 5' 5' 5' cycle 5' 5' 5' 5'

Singe stranded DNA RNA

5' Leftward oligonucleotide primer Nascent single stranded DNA

5' Rightward oligonucleotide primer HAE-P 01/13/2005 05:14PM Page 188

188 positron emission tomography (PET scan)

Figure 61 Positron emission tomography. Imaging in a patient with Hodgkin’s disease: (a) a positron emission tomography (PET) scan showing a increased signal in the chest (isotope concentrated in the kidneys and bladder is normal); (b) CT scan showing that the increased signal is the result of a mass of lymph nodes behind the heart.

(a)

(b)

encoding uroporphyrinogen decarboxy- between alternatives—expressed, for lase; enzyme activity may be reduced and example, as an 80% chance that accrual the disease precipitated by haemochro- of a given number of patients to a clin- matosis, alcohol excess, oestrogen intake ical trial will be able to demonstrate a or hepatitis C infection 5% difference in median survival with a positron emission tomography (PET probability level of P = 0.05; trials or scan) an imaging technique using experiments of inadequate power lead 18F-fluorodeoxyglucose position emission to the likelihood of a β error, i.e. that a tomography to detect glycolysis in meta- real difference will be missed bolically active tissue such as lymphoma POZ domain a highly conserved zinc (Fig. 61) finger domain, also known as the BTB post-partum occurring after childbirth (Bric a brac, Tramtrack, Broad complex) post-transfusion purpura thrombocy- domain, present on a wide range of pro- topenic purpura occurring usually 7–10 teins, e.g. PZLF and BCL6, which can days after a blood transfusion as a result mediate dimerization, transcriptional of the development of alloantibodies to repression by the recruitment of histone the human platelet antigen HPA-1a deacetylases, and nuclear microspeckled power the ability of an experiment or a localization clinical trial to detect a real difference PPD purified protein derivative HAE-P 01/13/2005 05:14PM Page 189

Product liability 189

PPP platelet-poor plasma primary immune response the im- PR partial remission munological response which occurs on PRAD1 an alternative designation of first exposure to an antigen BCL1 primary karyotypic abnormality the pRB the protein encoded by the tumour initial chromosomal abnormality occur- suppressor gene, TP53 ring in a clone of cells and present at pre-B cell (i) a lymphoid cell of B line- disease onset, e.g. t(9;22) in chronic age with cytoplasmic µ chain but lack- granulocytic leukaemia ing surface membrane immunoglobulin primary mediastinal B-cell lymphoma (as defined by EGIL) or (ii) any B-cell a large B-cell lymphoma of the medi- precursor astinum, probably originating in thymic precursor a cell which precedes another B cells and gives rise to it by a process of prolifer- primary proliferative polycythaemia ation and maturation an alternative designation of polycythaemia pre-eclamptic toxaemia (PET) pre- rubra vera gnancy-associated hypertension but with- primary thrombocythaemia an alter- out epileptiform convulsions (which native designation of essential thrombo- would indicate eclampsia rather than pre- cythaemia eclampsia), may be associated with a primary tumour a tumour at the site microangiopathic haemolytic anaemia where it initially developed preleukaemia the phase before leuk- primed in situ hybridization (PRINS) aemia develops when a preleukaemic a technique for identifying specific disorder may be recognizable, more or chromosomes by means of primers, less synonymous with ‘myelodysplastic which are annealed to target α satellite syndrome’ chromosome-specific repetitive DNA preleukaemic predisposing to or pre- sequences followed by in situ primer ceding leukaemia extension using Taq DNA polymerase pre-partum occurring during pregnancy, and incorporating fluorochrome-labelled before delivery dUTP prevalence the number of cases of a primer a short oligonucleotide sequence condition present in a community at any that provides the starting point for pro- one time, often expressed as the number ducing a complementary strand of DNA per 100 000 of population or RNA under the influence of DNA primary occurring of itself, not caused polymerase or reverse transcriptase by any external influence, occurring first PRINS primed in situ hybridization primary acquired sideroblastic proband index case anaemia an alternative designation of pro-B cell an immature lymphoid cell refractory anaemia with ring sideroblasts,a of B lineage that does not express CD10 FAB category of myelodysplastic syndrome or cytoplasmic or surface membrane primary amyloidosis light chain- immunoglobulin associated amyloidosis; the term, which is probe a labelled oligonucleotide that can now less used, was mainly applied to cases be used to identify a complementary without an overt plasma cell neoplasm sequence of DNA or RNA primary antiphospholipid syndrome PROC the gene at 2q13-q14, Protein C, a clinical syndrome with a thrombotic that encodes protein C, mutation of tendency and recurrent miscarriages caused which can lead to protein C deficiency by the presence of a lupus anticoagulant Product liability the liability of a but without the features necessary for a manufacturer—including manufacturers, diagnosis of systemic lupus erythematosus suppliers and keepers of blood products— primary granules the azurophilic under the terms of the UK Consumer granules that appear at the promyelocyte Protection Act 1987 for harm resulting stage of granulocyte maturation from any defect in a product HAE-P 01/13/2005 05:14PM Page 190

190 proerythroblast

proerythroblast the earliest morpho- prorubricyte an alternative designation logically recognizable cell in the erythroid of an early erythroblast lineage (see Fig. 25, p. 95) PROS1 the gene at 3p11.1-q11.2, Protein prophase the first stage of mitosis in S, that encodes protein S, mutation of which the chromosomes condense and which can lead to protein S deficiency become visible within the nucleus (see prostate-specific antigen an antigen Fig. 6, p. 14) expressed by prostatic cancer cells prometaphase the second of the five and sometimes by cells of large bowel stages of mitosis in which the two chro- adenocarcinoma matids of each chromosome become prostate-specific acid phosphatase visible an antigen expressed by prostatic cancer progenitor cell an early precursor cell cells capable of giving rise to later cells protamine sulphate a heparin antag- prognosis the likely outcome of an illness onist prognostic pertaining to prognosis protease an enzyme that breaks down proliferation the process of cell growth protein, see also proteinase and division leading to expansion of a protease inhibitors a group of drugs population of cells used to treat HIV infection proliferation centre a focal accumula- proteasome a ubiquitin-dependent mul- tion of larger nucleolated lymphocytes ticatalytic cytoplasmic complex, which is in a lymph node in chronic lympho- the main non-lysosomal mechanism for cytic leukaemia or small lymphocytic the degradation or processing of intracel- lymphoma lular proteins—both damaged cellular prolymphocyte an abnormal lymphoid proteins and short-lived regulatory cell which is larger than a normal lym- proteins—which are then either further phocyte and has plentiful cytoplasm and degraded in the cytosol to amino acids a large prominent nucleolus; the char- or are transferred into the endoplasmic acteristic cell of B and T-lineage prolym- reticulum phocytic leukaemia (see Fig. 14, p. 31) proteasome inhibitor an inhibitor of promonocyte a monocyte precursor the proteasome; proteasome inhibitors derived from a monoblast and giving rise lead to cell cycle arrest and apoptosis and to monocytes have therapeutic potential in haemato- promoter a sequence of DNA at the 5′ logical neoplasms end of a gene which is essential for initia- protein a three-dimensional structure tion of transcription (see Fig. 73, p. 221) formed by folding of a polypeptide chain promyelocyte an immature cell of gran- proteinase an enzyme that breaks down ulocytic lineage, derived from a myelo- protein, see also protease blast and giving rise to myelocytes (see proteinase 3 a protease which is Fig. 25, p. 95) one of the constituents of azurophilic properdin a protein in the alternative granules of neutrophils, also known as complement pathway myeloblastin prophylactic intended to prevent disease; protein C a vitamin K-dependent natu- however ‘prophylactic cranial irradia- rally occurring anticoagulant, encoded by tion’ in acute lymphoblastic leukaemia is, the PROC gene; after activation by the strictly speaking, treatment of occult dis- thrombin–thrombomodulin complex on ease rather than prophylactic treatment the surface of endothelial cells, and with prophylaxis prevention of disease or protein S and non-activated factor V as protection against disease cofactors, activated protein C inactivates propositus index case factors Va and VIIIa; activated protein C proptosis protrusion of an eye is a serine protease; in heterozygotes (3 prorubriblast an alternative designa- per 1000 prevalence in the general popu- tion of a proerythroblast lation), deficiency leads to thrombophilia, HAE-P 01/13/2005 05:14PM Page 191

pulmonary embolus 191

particularly if factor V Leiden is co- prothrombin deficiency an inherited, inherited; homozygotes are prone to autosomal recessive, deficiency of pro- neonatal purpura fulminans (see Fig. 56, thrombin, resulting from mutation in the p. 170) F2 gene protein–calorie malnutrition a lack prothrombin time (PT) a test of the of both protein and total calories leading extrinsic pathway of coagulation to the clinical presentations of marasmus protocadherin a subfamily of the ‘non- and kwashiorkor classical’ cadherins, encoded by 3 clusters protein S a vitamin K-dependent natur- of genes at 5q31 ally occurring anticoagulant, encoded by proto-oncogene a cellular equivalent the PROS1 gene; the major part of circu- of an oncogene of a transforming virus lating protein S is bound to C4b-binding PRP platelet rich plasma protein, with the bound protein S possibly Prussian blue a stain for iron, the basis having a role in localizing complement of the Perls’ stain regulatory activity to certain cell surfaces; pseudo- false free protein S is a cofactor of activated pseudodiploid a karyotype with 46 protein C; protein S also has a protein chromosomes but with structural or other C-independent anticoagulant effect, abnormalities, e.g. coexisting monosomy interacting with factor Va, Xa and pho- 7 and trisomy 8 would give a pseudodiploid spholipid to inhibit thrombin generation; karyotype as would the occurrence of a heterozygous protein S deficiency (i.e. translocation deficiency of free protein S with or with- pseudo-Gaucher cells storage cells out deficiency of total protein S) leads resembling Gaucher’s cells but not result- to thrombophilia while homozygotes are ing from Gaucher’s disease prone to neonatal purpura fulminans pseudogene a DNA sequence that proteinuria the presence of protein in resembles a gene but lacks genetic function the urine pseudolymphoma a term previously protein Z a vitamin K-dependent natur- used to designate a chronic unexplained ally occurring anticoagulant, encoded by proliferation of B lymphocytes which is the PZ gene, which binds to factor Xa, now considered to represent a low grade in association with phospholipid, and B-cell neoplasm serves as a cofactor for its inactivation by pseudo-Pelger–Huët anomaly ac- protein-Z dependent protease inhibitor quired Pelger–Huët anomaly proteoglycan a post-translationally pseudopolycythaemia apparent poly- modified protein in which a glycosamino- cythaemia, consequent on reduction of glycan chain is covalently linked to an the plasma volume, less appropriately amino acid residue referred to as ‘stress polycythaemia’ proteomics the quantification of and the PT prothrombin time functional analysis of all the proteins PU.1 a transcription factor, which is encoded by an organism’s genome (see expressed by neoplastic cells in nodular also structural proteomics) lymphocyte predominant Hodgkin’s dis- prothrombin a coagulation factor, ease but not by neoplastic cells of classical also known as factor II, encoded by Hodgkin’s disease or T-cell-rich B-cell the F2 gene; it is activated by factor Xa lymphoma in the presence of factor V and pho- pulmonary pertaining to the lungs spholipid; on activation, it is known pulmonary embolism the process of as thrombin (see Figs 17 and 18, pp. 77 embolization of the lungs and 78); a common polymorphism in pulmonary embolus a blood clot the 3′-untranslated region of the F2 gene which has become detached from a (20210→Α) leads to an increased plasma peripheral vein or from the right side prothrombin concentration and an of the heart and has travelled to the increased probability of thrombosis lungs HAE-P 01/13/2005 05:14PM Page 192

192 pulsed ﬁeld gel electrophoresis (PFGE)

pulsed field gel electrophoresis P < 0.05 means that the probability of (PFGE) an electrophoretic technique the observation occurring by chance is for separating large proteins by periodic- less than 1 in 20 ally altering the direction of the electric pyknosis the process by which a nucleus field through which they are migrating becomes dense and homogeneous prior PUO pyrexia of unknown origin to cell death pure red cell aplasia a lack of erythroid pyrexia fever cells beyond the proerythroblast stage but pyrexia of unknown origin (PUO) with no significant abnormality of other fever of which the cause is unknown lineages pyrimidine one of the two types of purified protein derivative (PPD) a nitrogenous base found in nucleic acids; blood product composed mainly of pyrimidines (cytosine, thymine and albumin uracil) have a single ring structure; see purine one of the two types of nitroge- also purine nous base found in nucleic acids; purines pyrimidine 5′ nucleotidase an ery- (adenine and guanine) have a double ring throcyte enzyme involved in nucleotide structure; see also pyrimidine metabolism; deficiency leads to haemo- purpura subcutaneous or submucosal lytic anaemia with prominent basophilic haemorrhage, classified as ecchymoses stippling and petechiae pyropoikilocytosis see hereditary pyro- purpura fulminans extensive purpura poikilocytosis and skin necrosis resulting from thrombo- pyruvate kinase an enzyme in the sis; may be a consequence of severe defici- glycolytic pathway which catalyses the ency of protein S, protein C or (rarely) conversion of phosphoenolpyruvate to antithrombin or may result from mening- pyruvate, encoded by the PKLR gene at ococcaemia or disseminated intravascular 1q21; the PKLR gene encodes both liver coagulation and red cell pyruvate kinase by means of P value the statistical probability two tissue-specific promoters (see Fig. 33, attached to a certain observation, e.g. p. 113) HAE-Q 01/13/2005 05:15PM Page 193

5q− syndrome a specific subtype of q− a chromosome with loss of material myelodysplastic syndrome, defined in the from its long arm WHO classification as having 5q– as an Q-banding a technique for producing isolated abnormality and blast cells less a banded pattern on chromosomes by than 5% in both blood and bone marrow staining with quinacrine q the long arm of a chromosome Q fever a disease resulting from a rick- q+ a chromosome with addition of mater- ettsial infection (by Coxiella burnetti) ial to its long arm

193 HAE-R 01/13/2005 05:15PM Page 194

r a cytogenetic abbreviation for a ring Figure 62 A radiograph of the skull. chromosome A radiograph of the skull showing lytic lesions in a RA refractory anaemia patient with multiple myeloma. Rabaptin-5 a gene, gene map locus 17q13, that encodes a protein which is an important regulator of early endosomal transport through interaction with the RAS family GTPases, Rab5 and Rab4; it contributed to a Rabaptin5-PDGFRB fusion gene in a patient with chronic myelomonocytic leukaemia; the fusion protein oligomerizes on account of the coiled-coil domains of rabaptin-5 leading to constitutive activation of the tyrosine kinase moiety of PDGFRB RAC1 a gene, RAS-related C3 botulinum toxin substrate 1, gene map locus12q13.12, encodes a small GTP-binding protein; a member of the Rho family of RAS-like signalling molecules; RAC1 is a key radiotherapy the treatment of disease, regulator of cadherin-mediated cell– particularly neoplastic disease, by means cell adhesion; it has inherent low level of X-rays or gamma rays GTPase activity which is augmented by RAEB refractory anaemia with excess of the BCR protein blasts radiation α or β particles or γ rays; γ rays RAEB-T refractory anaemia with excess are also known as X-rays of blasts in transformation radioactive giving off radiation as the RAG1 and RAG2 two Recombina- result of disintegration of the nucleus tion Activating Genes which mediate radioactive isotope a form of an ele- the process of V(D)J recombination lead- ment which is radioactive but otherwise ing to the assembly of antigen-receptor has very similar qualities to other forms genes encoding immunoglobulin and T- of the element, often used in diagnosis cell receptors; mutation leads to severe and treatment combined immunodeficiency (SCID) and radiograph an image produced by Omenn’s syndrome means of X-rays passing through a part RAMP a gene, Rearranged in an Atypical of the body to expose part of a photo- Myeloproliferative disorder, an altern- graphic film, popularly known as an X- ative designation of ZNF198 ray (Fig. 62) random occurring by chance radioimmunoassay (RIA) a laboratory random chromosomal abnormality technique for determining the concen- a chromosomal abnormality occurring in tration of an antigen or antibody in the a single cell or not meeting the criteria for serum by means of a radio-labelled reagent definition of a clonal abnormality 194 HAE-R 01/13/2005 05:15PM Page 195

RB1 195

randomized trial a comparison of RARS refractory anaemia with ring sider- two or more forms of therapy in which oblasts treatment is assigned randomly; see also RAS a family of genes, Rat Sarcoma viral double blind oncogene homologue, encoding three RAP1GDS1 a gene, GTPase-GDP Dis- related p21RAS proteins, H-RAS (gene sociation Stimulator 1, gene map locus map locus 11p15.5), K-RAS (gene map 4q21, encodes a stimulatory GDP/GTP locus 12p12.1) and N-RAS (gene map guanine nucleotide exchange factor (GEF) locus 1p13.2); archetypal members of a with GTPase activity; contributes to a larger superfamily of at least 100 related NUP98-RAP1GDS1 fusion gene fusion small GTP-binding proteins which gene in t(4;11)(q21;p15) associated with function as simple ‘on/off’ molecular 3% of adult cases of T-lineage acute switches, activated by GTP binding and lymphoblastic leukaemia; the chimaeric inactivated by hydrolysis of GTP to protein, which consists of the FG repeat- GDP; have low-level intrinsic GTPase rich region of NUP98 fused to the entire function which is augmented by GTPase coding region of RAP1GDS1, is found activating proteins (GAPs), which lead in both the cytoplasm and the nucleus. to their activation; RASGRP4 encodes RARA a gene, Retinoic Acid Receptor a myeloid speciﬁc GEF for RAS proteins; Alpha, gene map locus 17q12, encodes small GTP-binding proteins regulate a transcriptional regulator which is a diverse functions such as receptor medi- nuclear receptor for all-trans retinoic acid ated signalling and cytoskeletal organiza- (ATRA) and 9-cis retinoic acid (cRA); it tion; N-RAS and K-RAS mutations are belongs to a subfamily of the nuclear common as second events in many cancers receptor group of ligand-activated tran- including multiple myeloma, acute lym- scription factors that also includes RARβ phoblastic leukaemia (20–30% of cases) and RARγ; each RAR encodes 2 isoforms and myeloid neoplasms (20–30% of cases which differ at their amino termini; RARs of acute myeloid leukaemia, 15–20% bind to speciﬁc DNA sequences called of myelodysplastic syndromes—particu- retinoic acid response elements (RAREs), larly in those with a poor prognosis— but only when heterodimerized to an and chronic myeloid leukaemia, 20% of RXR (α, β or γ); in the absence of ligand atypical chronic myeloid leukaemia); the RXR/RAR complex acts as a tran- K-RAS is often mutated in carcinoma scriptional repressor by recruiting his- (e.g. 90% of pancreatic carcinomas and tone deacetylases, but in the presence of 60% of colonic carcinomas) whereas retinoids the complex acts as an activ- N-RAS is characteristically mutated in ator; RARA contributes to: myeloid neoplasms; drugs designed to •a PML-RARA fusion gene in interfere with the oncogenicity of RAS- t(15;17)(q22;q21) associated with M3 and encoded proteins are under development M3 variant acute myeloid leukaemia RB1 a gene, Retinoblastoma 1, gene map •a PLZF-RARA fusion gene in locus 13q14, encodes the ubiquitously t(11;17)(q23;q21) associated with M3- expressed archetypal member of a family like acute myeloid leukaemia of proteins that link signals controlling •a NuMA-RARA fusion gene in the cell cycle to the nuclear transcriptional t(11;17)(q13;q21) in rare cases of M3-like apparatus; a candidate tumour suppres- acute myeloid leukaemia sor gene; RB1 inhibits the progression •a NPM-RARA fusion gene in from G1 to S phase of the cell cycle; the t(5;17)(q32;q21) associated with rare inhibition of the E2F transcription factor cases of M3-like acute myeloid leukaemia by RB1 is key to this growth-suppressing •a STAT5b-RARA fusion gene action; RB1 is phosphorylated by cyclin described in one patient with der(17) and D/CDK4 and once phosphorylated is M1 acute myeloid leukaemia unable to interact with E2F; wildtype p53 •a MLL-RARA fusion gene in M5 acute suppresses transcription of RB1; implicated myeloid leukaemia with t(11;17)(q23;q12) in familial retinoblastoma and possibly in HAE-R 01/13/2005 05:15PM Page 196

196 RBC

the progression of chronic lymphocytic map locus 11q23.3, encodes an RNA leukaemia (although another gene at 13q14 helicase which contains the evolutionar- may be more relevant), acute myeloid ily conserved Asp-Glu-Ala-Asp (DEAD) leukaemia and acute lymphoblastic leuk- box sequence (see also DEAD box and aemia; deleted in about 50% of patients DDX10); dysregulated by proximity to with T-cell prolymphocytic leukaemia but the IGH locus in t(11;14)(q23;q32) associ- other sequences at 13q14 are more often ated with B-cell malignancy deleted; deleted in some patients with RDW red cell distribution width multiple myeloma; loss or mutation of RB1 reactive an abnormality that is a occurs in up to 30% of patients with blast response to another primary disease or crisis of chronic granulocytic leukaemia pathological process RBC red blood cell count REAL classification the Revised RBM15 a gene, RNA-Binding Motif pro- European–American Lymphoma clas- tein 15, gene map locus 1p12, also known sification as OTT, has homology to Drosophila spen real time PCR (RQ-PCR) a semiquantit- and encodes a protein that interacts with ative PCR technique in which estimation RAS and E2F; it contributes to RBM15- of the rate of generation of the product MKL1 and MKL1-RBM15 fusion genes during the exponential phase permits in acute megakaryoblastic leukaemia of quantification of the amount of the target infants with t(1;22)(p13;q13); it is the DNA originally present (Fig. 63); RQ- RBM15-MKL1 fusion gene which is PCR techniques include Taq-Man and likely to be oncogenic; the chimaeric pro- Dye intercalation tein generated by this fusion contains all rearrangement the process by which putative functional motifs encoded by the structure of a chromosome or a gene each gene is altered by means of breaking and RBTN1 a gene, Rhombotin-1, also known rejoining of sequences of DNA in one or as LIM domain Only 1 (LMO1) and T- more chromosomes; rearrangement may cell Translocation Gene 1 (TTG1), gene be a normal process, in antigen recogni- map locus 11p15, encodes a LIM domain tion by lymphoid cells, or a pathological transcriptional regulator which is a process which, in some circumstances, nuclear partner of SCL and which is leads to neoplastic transformation of a important in T-cell development; RBTN1 cell and clonal proliferation is dysregulated, possibly by proximity to receptor tyrosine kinase (RTK) a trans- the TCRAD (αδ) locus, in T-lineage acute membrane protein with an extracellular lymphoblastic leukaemia associated with ligand-binding domain, a transmembrane t(11;14)(p15;q11) domain and an intracellular domain that, RBTN2 a gene, Rhombotin-2, also known on activation of the protein, can phos- as LIM domain Only 2 (LMO2) and T- phorylate tyrosine residues on substrate cell Translocation Gene 2 (TTG2); gene proteins map locus 11p13; encodes a LIM domain recessive a mode of inheritance in which transcriptional regulator which is a nuclear a characteristic or a disease occurs in partner of SCL and which is important in homozygotes or compound heterozygotes haemopoiesis and vasculogenesis; RBT2 but not in simple heterozygotes is dysregulated by: reciprocal translocation a transloca- • proximity to the TCRB gene in T- tion in which segments of chromosome lineage acute lymphoblastic leukaemia are exchanged between two (or more) associated with t(7;11)(q35;p13) chromosomes (see also balanced translo- • by proximity to the TCRAD (αδ) cation and unbalanced translocation) locus in T-lineage acute lymphoblastic recombinant coagulation factors leukaemia associated with t(11;14)(p13;q11) coagulation factors, e.g. factor VIII, RCK a gene, also known as DEAD/H box factor IX or factor VIIa, produced by 6 (DDX6) and RNA helicase p54, gene inserting a human gene into a mam- HAE-R 01/13/2005 05:15PM Page 197

recombinant coagulation factors 197

Figure 63 Real-time Polymerase Chain Reaction (RQ-PCR). There are a number of techniques available which make a PCR semi-quantitative. These depend on the kinetics of PCR and include intercalating dye technology and Taqman™ RQ-PCR. (a) Kinetics of PCR—as long as the reaction substrates or the activity of the enzyme are not limiting, the amount of product that is generated in a PCR, which can be measured by a fluorescence method, doubles after every cycle. Each product molecule is itself able to act as a template in the next round of amplification. Depending on the amount of template at the start, the efficiency with which the primers anneal and the activity of the enzyme, after a certain number of cycles in any PCR, the amount of product generated per cycle increases in a linear fashion (the exponential phase). It is during this phase that real time PCR systems are able to quantify and compare the amounts of products made in different reactions. Eventually the amount of new product generated per cycle decreases to zero (plateau phase). This occurs when either enzyme or substrates become limiting. (b) Intercalating dye technology—an intercalating dye, e.g. SybrGreen™, fluoresces only when it binds to double stranded DNA. Fluorescence is proportional to the amount of double stranded DNA (PCR product). (c) (overleaf ) Taqman™ technology—the PCR is carried out using a thermostable polymerase with ‘proof- reading’ (5′ to 3′ exonuclease) activity. An oligonucleotide probe complementary to a short stretch of the DNA to be amplified is added to the reaction. The probe has a fluorescent ‘reporter’ group (R) and a ‘quencher’ (Q) covalently bound to its ends. The physical proximity of the Q group to the R group in the intact molecule suppresses the fluorescence of the latter. If the probe hybridizes to the template during the extension phase of the PCR, then it will be degraded by the exonuclease activity of the enzyme. This separates the reporter and quencher and allows the reporter to fluoresce. Fluorescence is proportional to the amount of free reporter which in turn depends upon the amount of specific amplified product to which the probe can hybridize.

100% Plateau phase High abundancy template Intermediate abundancy template Low abundancy template 75% Exponential phase 50%

25% Amount of product (fluorescence) 0% 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 (a) Number of completed cycles of amplification

Dye molecules intercalate in DNA and fluoresce (b)

(Continued) HAE-R 01/13/2005 05:15PM Page 198

198 recombinant DNA

5' 3' Template DNA or nascent PCR product Probe QR 5' Oligonucleotide primer

Polymerase

5' 3' 5'

Newly synthesized DNA Q Reporter fluoresces (c) R

malian cell line which is then grown in red cell survival the time for which red culture on an industrial scale cells survive in the circulation, normally recombinant DNA a DNA molecule in about 120 days which rearrangement of genes has been red marrow haemopoietic marrow artificially induced which is red in colour, in adults found in recombination (i) the occurrence of a the vertebra, sternum, ribs, clavicles and new combination of linked genes as a proximal long bones (cf. yellow marrow) result of cross-over between homologous Reed–Sternberg cell a binucleated chromosomes at meiosis (ii) the rearrange- giant cell with giant nucleoli that is part ment of the regions of an immunoglo- of the neoplastic population in Hodgkin’s bulin or T-cell receptor gene (see Fig. 46, disease p. 135) reference range the range of laborat- red cell an erythrocyte, a non-nucleated ory values found in a carefully defined cell of the peripheral blood the main func- reference population, usually expressed tion of which is the transport of oxygen as a 95% range red cell count (RBC) the number of red refractory not responsive to treatment cells in a defined volume of blood refractory anaemia (RA) one of the red cell distribution width (RDW) an myelodysplastic syndromes; cases of RA estimate of anisocytosis produced by in the FAB classification are assigned to automated full blood counters either refractory anaemia or refractory red cell indices a term which usually cytopenia with multilineage dysplasia in indicates: RBC, Hb, PCV, MCV, MCH the WHO classification (see Table 13, and MCHC p. 167) red cell mass the total volume of red cells refractory anaemia with excess of in the circulation, determined by radio- blasts (RAEB) one of the myelodys- isotopic dilution techniques and expres- plastic syndromes; cases of RAEB in the sed either as ml/kg or as a percentage of FAB classification are generally assigned what is expected in a person of the same to either RAEB-I or of RAEB-II in the height and weight WHO classification (see Table 13, p. 167) red cell membrane the lipid bilayer refractory anaemia with excess of with many specialized molecules bearing blasts in transformation (RAEB-T) antigenic determinants which encloses one of the myelodysplastic syndromes, the red cell (Fig. 64) according to the FAB classification; in the HAE-R 01/13/2005 05:15PM Page 199

relative risk 199

Figure 64 The red cell membrane. A diagram illustrating the structure of the red cell membrane; protein or glycoprotein molecules project from or pass through the lipid bilayer that encloses the cell. The transmembrane molecules (band 3 and glycophorin C) are linked to molecules of the cytoskeleton, which maintains the shape and yet permits the ﬂexibility of the cell.

Glycophorin A Glycophorin A

Band Band 3 3

Actin Lipid bilayer Tropomysin 4.1 α β Protein 4.2 4.9 Ankyrin Adducin 4.1 β α 4.1 α β β spectrin Tropomodulin α spectrin

WHO classification these patients are encoded by RELA (gene map locus classified as acute myeloid leukaemia if 11q12-q13), and RELB (gene map locus they have more than 20% of blast cells 19q13.32), which heterodimerize with in the peripheral blood or bone marrow either NFκB1 or NFκB2 to form NFκB or are classified as myelodysplastic syn- transcription factors which recognise drome, RAEB-II if they have Auer rods specific DNA-binding sites (κB sites); in but fewer blasts (see Table 13, p. 167) addition c-REL and RELA, but not refractory anaemia with ring siderob- RELB, can form homodimers; the term lasts (RARS) one of the myelodysplastic NFκB is often used for the NFκB1p50- syndromes; cases classified as RARS in RELA heterodimer, which is the major the FAB classification are classified, in the REL complex in most cells; NFκB is WHO classification as either RARS or constitutively activated in Hodgkin and refractory anaemia with multilineage dys- Reed–Sternberg cells and this may relate plasia and ring sideroblasts (see Table 13, to duplication of 2p; REL is amplified in p. 167) mediastinal large B-cell lymphoma. refractory cytopenia a FAB category REL a domain homologous to retroviral of the myelodysplastic syndrome, refer- v-rel that characterizes a family of tran- ring to cases with either neutropenia or scription factors including BCL3 thrombocytopenia that do not meet the relapse the recurrence of a disease criteria for any other category of MDS relapsing fever illness caused by rejection the immunological process Borrelia species, characterized by an leading to destruction of engrafted tissue intermittent fever REL a gene, avian Reticuloendotheliosis relative risk the odds ratio, the ratio of viral oncogene homologue, gene map the likelihood of a disease in a group locus 2p13-p12; encodes c-REL, one of exposed to a particular hereditary or three related proteins, the others being environmental influence to the risk in a HAE-R 01/13/2005 05:15PM Page 200

200 remission

group not so exposed; an odds ratio of 2 reticulin a fibrillar protein which forms would indicate that the likelihood of part of the bone marrow stroma, iden- the disease was increased twofold in the tified by its argyrophilia (uptake of silver) exposed group reticulocyte a young erythrocyte, newly remission the regression of a disease, released form the bone marrow, iden- may be a partial remission or complete tified by its uptake of certain vital stains remission such as new methylene blue renal pertaining to the kidney reticulocyte count quantification of renal osteodystrophy bone disease reticulocytes as a proportion of total consequent on chronic renal failure, erythrocytes or in a defined volume of caused by a combination of vitamin D blood deficiency and hyperparathyroidism reticulocytopenia a low reticulocyte replicate to make copies of oneself, as count in replication of a strand of DNA or a reticulocytosis a high reticulocyte chromosome count replication the process of making copies reticuloendothelial system (RES) a of oneself, e.g. the copying of DNA, in collective name for macrophages and which a single strand serves as a tem- related cells distributed throughout the plate for the synthesis of a comple- body but particularly in the liver and mentary strand, thus recreating the spleen double-stranded molecule reticulum cell a bone marrow stromal reporter gene a gene encoding a prod- cell, probably of two distinct lineages, uct that can be detected easily after phagocytic reticulum cells being of transfection macrophage lineage and non-phagocytic RES reticuloendothelial system reticulum cells of mesenchymal origin, respiratory burst a burst of metabolic probably being related to fibroblasts and activity in phagocytes which leads to the the adventitial cells of sinusoids sequential reduction of oxygen to pro- reticulum cell sarcoma an outmoded duce toxic oxygen metabolites such as term for large cell lymphoma hydrogen peroxide, hydroxyl radicals retinoblastoma a malignant tumour of and singlet oxygen the retina restriction endonuclease an enzyme retrovirus a group of RNA viruses con- capable of cleaving DNA only at speci- taining reverse transcriptase in the virion, fic internal sites determined by DNA includes the oncogenic human virus, sequence HTLV-I, and also a number of viruses restriction enzyme see restriction causing leukaemia in various animals endonuclease reverse transcriptase an enzyme restriction fragment a fragment of which permits the synthesis of cDNA DNA produced by cleavage by a restric- from an RNA template, RNA-dependent tion endonuclease DNA polymerase; it is encoded by genes restriction fragment length poly- of RNA viruses and is used experi- morphism (RFLP) variation between mentally in the reverse transcriptase poly- homologous chromosomes with regard merase chain reaction (RT-PCR) to the length of DNA fragments pro- reverse transcriptase-polymerase duced by application of a specific restric- chain reaction (RT-PCR) a technique tion endonuclease; can be used for the for amplifying DNA that had first been demonstration of heterozygosity and for synthesized from an RNA template by studies of clonality or for demonstration means of reverse transcriptase of a specific gene that removes or creates RFLP restriction fragment length a specific cleavage site polymorphism reticular agenesis an inherited disorder Rh a complex system of at least 45 blood when all leucocytes are lacking group antigens (CD240CE, CD240D, HAE-R 01/13/2005 05:15PM Page 201

ring chromosome (r) 201

Table 15 Rh genotypes, phenotypes and shorthand notations or describing the genotype.

Most likely genotype among Most likely genotype among Rh antigens Caucasians (alternative Caucasians (genes described expressed Phenotype practical terminologies) according to current terminology)

CDce CcDee CDe/cde R1r D + Ce/d + ce CDe CCDee CDe/CDe R1R1 D + Ce/D + Ce cDEe ccDEe cDE/cde R2r D + cE/d + ce cDE ccDEE cDE/cDE R2R2 D + cE/D + cE CcDEe CcDEe CDe/cDE R1R2 D + Ce/D + cE cDe ccDee cDe/cde R0r D + ce/d + ce ce ccee cde/cde rr d + ce/d + ce Cce Ccee Cde/cde r′r d + Ce/d + ce cEe ccEe cdE/cde r′′r d + cE/d + ce CcEe CcEe Cde/cdE r′r′′ d + Ce/d + cE

CD240DCE, CD241), expressed only on Rh-null the failure to express any Rh red cells, previously known as the Rhesus antigens; this can result from null alleles blood group system (Table 15) at the RH locus or from homozygosity rhabdomyosarcoma a malignant for an X chromosome regulator gene tumour of muscle cells RhoH see TTF RHCE a gene at 1p36.2-p34 which has Rh-positive having the Rh D antigen four main alleles, CE, Ce, cc and cE, RIA radioimmunoassay encoding C + E, C + e, c + e and c + E ribonucleic acid (RNA) a polynucleo- RHD a gene at 1p36.2-p34 encoding the tide in which the nitrogenous bases are Rh D antigen, a non-glycosylated trans- adenine, guanine, cytosine and uracil and membrane protein: reduced expression the sugar is ribose; RNA is produced in leads to a DU phenotype; a partial D phe- the nucleus and in mitochondria from notype is one in which some epitopes of DNA templates the D antigen are lacking; homozygous ribosomal lamellar complex an organ- deletion of the RHD gene and certain elle composed of concentric layers of mem- mutations of the gene lead to the dd branes to which ribosomes are attached, phenotype characteristic of hairy cell leukaemia Rhesus see Rh ribosomal RNA (rRNA) RNA that, rheumatoid arthritis a chronic together with protein, constitutes the inﬂammatory arthritis, autoimmune in ribosomes nature; haematological features include ribosome a cytoplasmic structure on anaemia, which may be normocytic and which proteins are translated from normochromic or microcytic and hypo- messenger RNA; ribosomes may be free chromic, an elevated erythrocyte sed- within the cytosol or form part of the imentation rate and, sometimes, Felty’s rough endoplasmic reticulum syndrome ribozyme an RNA molecule that can rheumatoid factor an autoantibody, cleave single-stranded RNA usually IgM, directed at IgG, present in Richter’s syndrome a high grade large the serum in rheumatoid arthritis cell transformation of chronic lympho- RH locus a locus at 1p36.2-p34 with two cytic leukaemia highly homologous very closely linked right shift increased segmentation of genes, RHD and RHCE neutrophils Rh-negative lacking the Rh D antigen ring chromosome (r) an abnormal —dd chromosome in the shape of a ring HAE-R 01/13/2005 05:15PM Page 202

202 ring chromosome (r)

Figure 65 RNA processing. Newly transcribed (nascent) RNA must undergo several enzymatic modifications (processing) before it is exported from the nucleus as messenger RNA (mRNA). For simplicity, the steps in this process are depicted as occurring after transcription, but it is known that they occur during transcription itself (see Figure 73, p. 221). These modifications to nascent RNA (pre mRNA) comprise (i) Addition of a cap structure to the 5′ end of the RNA which occurs after about 30 nucleotides have been added. The triphosphate of the first base is hydrolyzed to a diphosphate; then the GMP moiety from a GTP substrate is joined by a 5′–5′ triphosphate bond to the first nucleotide of the nascent RNA. The transferred GMP is then methylated at the N7 position to give a mature cap. The cap is recognized by proteins that export mRNAs into the cytoplasm. (ii, iii) Excision of introns and splicing together of exons occurs as nascent RNA is synthesised, and is catalysed by a structure called the spliceosome, composed of proteins and small nucleolar RNAs (snRNA). The 5′ exon/intron border (/) has the consensus sequence AG/GURAGU and the 3′ intron/exon border is YAG/RNNN (R = A or G, Y = U or C, N = A,G,C or U), in addition, all introns have a ‘branchpoint’ sequence about 100 bp from their 3′ ends containing a CURAY motif. Splicing occurs in two steps; the 2′OH of the branchpoint adenosine attacks the phosphodiester bond at the 5′ exon/intron boundary, freeing the 5′ exon and creating a panhandle (‘lariat’) structure comprising the intron and downstream exon; subsequently the 3′OH of the freed exon cleaves the downstream intron/exon border. (iv) Polyadenylation of the 3′ end of the nascent transcript is the final step in RNA processing and occurs in the mRNAs of all genes except histones. It involves the addition of about 250 adenosine residues and is triggered by a hexamer motif I (the polyadenylation signal) in the 3′UTR—AAUAAA. The polyadenylation signal and other sequence motifs in the 3′UTR are necessary for transcriptional termination. They permit the enzymatic cleavage of the nascent transcript, leading to its release from the RNA polymerase complex. This in turn allows the polymerase itself to leave the template.

Start Stop codon codon

Promoter Untranslated Exon region Intron Gene Flanking Flanking region region Transcription

AG/GURAGU CURAY YAG/RNNN AAUAAA 5' 3' Nascent RNA PP (ii) GTP (i) (iv) RNA processing (iii)

P U G Lariat A

Start Stop codon codon

MethylG5'ppp5'N AAAAAAn mRNA HAE-R 01/13/2005 05:15PM Page 203

RXRs 203

RING finger Really Interesting New rouleau (plural rouleaux) red cells Gene, a zinc-binding protein motif gen- stacked up like a pile of coins, indicative erally found close to an amino or car- of an increased concentration of immuno- boxy terminus and present in over 200 globulins or other plasma proteins, par- proteins including PML, BRCA1 and ticularly high molecular weight plasma ubiquitination enzymes; plays a key role in proteins the ubiquitination of other proteins prior RPL2 see EAP to their proteolysis (see also ubiquitin and RPN1 the Ribophorin gene, gene map ubiquitination) locus 3q21, encodes a ubiquitously ex- ring sideroblast or ringed sideroblast pressed ribosomal protein; the enhancers an erythroblast with a ring of siderotic of RPN1 are responsible for: granules surrounding its nucleus • dysregulation of EVI1 in acute myeloid ristocetin an antibiotic used in testing leukaemia associated with inv(3)(q21q26) for von Willebrand’s disease; ristocetin and t(3;3)(q21;q26) induces platelet aggregation in the pres- • dysregulation of the MEL1 gene in acute ence of von Willebrand’s factor myeloid leukaemia and myelodysplastic ristocetin cofactor assay a quant- syndrome associated with t(1;3)(p36;q21) ification of the ability of plasma to support RPS19 a gene encoding a ribosomal struc- ristocetin-induced platelet aggregation, tural protein, mutations of which cause indicative of the concentration of von some cases of Diamond–Blackfan syndrome Willebrand’s factor in the plasma RQ-PCR real time polymerase chain RNA ribonucleic acid reaction RNAi RNA interference rRNA ribosomal RNA RNA interference (RNAi) a process RTK receptor tyrosine kinase whereby introduction of double stranded RT-PCR reverse transcriptase polymerase RNA into a cell inhibits gene expression chain reaction in a sequence-dependent fashion rubella a viral infection; German measles RNA processing the process by which RUNX1 see AML1 and Fig. 22, p. 83 newly synthesized RNA is modified RUNX2 the approved name for AML3/ (Fig. 65) CBFA2 (see CBF and Fig. 22, p. 83) Robertsonian translocation a tran- RUNX3 the approved name for AML2/ slocation resulting in fusion of the long CBFA3 (see CBF and Fig. 22, p. 83) arms of two acrocentric chromosomes Russell body a large round cytoplasmic at the centromere, the short arms being inclusion composed of immunoglobulin in lost the cytoplasm of a plasma cell Romanowsky stain a stain composed RxFISH cross-species fluorescence in situ of a mixture of old methylene blue and hybridization eosin, initially devised by a nineteenth- RXRs genes encoding Retinoid X Recep- century parasitologist for staining malaria tors; a family of three retinoid receptors parasites; by extension, a stain based on (α, β or γ; gene map loci 9q34.3, 6p21.3 Romanowsky’s principle of mixing acidic and 1q22-q23 respectively) that have low and basic dyes; both May–Grünwald– ligand affinities, bind only the 9-cis isomer Giemsa and Wright’s stain are Romano- of retinoic acid and cannot autonomo- wsky stains usly induce transcription on binding; they rough endoplasmic reticulum endo- function as promiscuous heterodimeriza- plasmic reticulum to which many ribo- tion partners for many nuclear receptors, somes are attached, giving it a granular e.g. the vitamin D receptor, retinoic acid or ‘rough’ appearance; the rough endo- receptors (RARs) and the peroxisome plasmic reticulum is a site of protein proliferator-activated receptors (PPARs). synthesis HAE-S 01/13/2005 05:15PM Page 204

S the designation of the phase of the cell Figure 66 Scanning densitometry. cycle when synthesis of DNA occurs (see The application of scanning densitometry to cell cycle) quantitating serum proteins from an electrophoretic SACD subacute combined degeneration of strip: (a) normal showing, from right to left, albumin and α1, α2, β and γ globulins; (b) a sample from a the spinal cord patient with multiple myeloma showing a saline pertaining to salt, usually sodium paraprotein in the γ region and a reduction of normal chloride polyclonal immunoglobulins; (c) a sample from a saline solution a solution of sodium second patient with multiple myeloma showing a λ chloride large amount of a Bence Jones protein β λ Sanfilippo syndrome an inherited in the region (arrowhead) and an IgG paraprotein in the γ region (short arrow); the nature of the bands metabolic disorder, one of the muco- was determined by immunofixation. polysaccharidoses SAP an alternative name for the SH2DIA gene (see X-linked lymphoproliferative disease) SAP domain a motif present in proteins that recruit other proteins, involved in transcription and RNA processing, to the matrix attachment regions of chromatin sarcoidosis a granulomatous disorder SCF stem cell factor of unknown nature SCF a gene at 12q22-24, encoding stem sarcoma a malignant neoplasm of soft cell factor tissue cells such as osteocytes or fibroblasts Schilling test a test of absorption of

SBB Sudan black B vitamin B12, with and without intrinsic SC an abbreviation sometimes used to factor, performed using vitamin B12 indicate the presence of haemoglobin S labelled with a radioactive isotope and haemoglobin C but not recom- schistocyte an erythrocyte fragment mended because of its ambiguity Schuffner’s dots cytoplasmic inclu- SC a gene at 1p36.2-p34 encoding the sions in erythrocytes parasitized by Scianna blood group antigens Plasmodium vivax or Plasmodium ovale scanning electron microscopy (SEM) SCID severe combined immunodeﬁciency an electron microscopy technique that SCL an alternative designation of TAL1 produces an apparently three-dimensional scurvy the disease resulting from image (see Figs 4, 24, 43 and 69, pp. 5, 91, deﬁciency of vitamin C or ascorbic acid, 125 and 208 respectively) can cause anaemia and mucocutaneous scanning densitometry a process of haemorrhage optically scanning an electrophoretic SD standard deviation strip to quantitate the proteins present, Se an allele of FUT2, conveys secretor applicable to serum protein electro- status phoresis (Fig. 66) and haemoglobin se an allele of FUT2, conveys non- electrophoresis secretor status if homozygous

204 HAE-S 01/13/2005 05:15PM Page 205

SET domain 205

sea-blue histiocyte a storage cell con- sedimentation rate the erythrocyte taining ceroid or lipofuscin which can sedimentation rate occur in inherited metabolic disorders segmented neutrophil a mature neu- and also in various acquired conditions trophil with a nucleus divided into lobes sea-blue histiocytosis ceroid-lipofus- or segments cinosis, a group of inherited metabolic selectin one of a family of three cell disorders adhesion molecules, E-, L- and P-selectin Sebastian syndrome a giant platelet (CD62E, CD62L and CD62P) syndrome with thrombocytopenia and SEM scanning electron microscopy neutrophil inclusions, resulting from a semipermeable membrane a mem- mutation in the non-muscle myosin heavy brane that can be crossed by solvent but chain 9 gene (NMMHC-A or MYH9) at not solute 22q11-13 (or 22q12.3-q13.2) sensitivity the capacity of a test to detect secondary (i) having an external cause the presence of an abnormality (ii) jargon for a metastasis (iii) developing sepsis infection later septicaemia an acute illness associated secondary granules the specific gran- with bacteraemia ules of neutrophils, eosinophils and SEPTIN 2 a gene, also known as basophils KIAA00128, the homologue of mouse secondary immune response the septin 6, gene map locus Xq22, encod- immune response on a second or sub- ing a GTPase; SEPTIN2 contributed to sequent exposure to an antigen a MLL-SEPTIN 2 fusion gene in two secondary karyotypic abnormality a infants with acute myeloid leukaemia chromosomal abnormality occurring associated respectively with t(X;11;3;11) during the subsequent evolution of an and ins(X;11)(q24;q23) abnormal clone that already shows a pri- sequencing analysis of the sequence of mary karyotypic abnormality (see Fig. 49, bases in a DNA molecule p. 146) serous atropy gelatinous transforma- secondary leukaemia (i) leukaemia tion, deposition of increased ground secondary to exposure to anti-cancer substance or acid mucopolysaccharide chemotherapy or irradiation, usually in the bone marrow acute myeloid leukaemia but occasion- serpin one of a family of intracellular ally acute lymphoblastic leukaemia or and extracellular serine protease inhibi- acute biphenotypic leukaemia, also known tors including antithrombin, antiplasmin, α as therapy-related leukaemia (ii) more plasminogen activator inhibitor 1 and 2, 1 broadly, leukaemia following exposure to antitrypsin, C1 inhibitor mutagenic agents or occurring during the serum (plural sera) the liquid part of course of another haematological disorder blood that remains after clotting has led secondary myelodysplastic syndrome to the removal of fibrinogen a myelodysplastic syndrome secondary serum protein electrophoresis the to exposure to anti-cancer chemotherapy separation of the proteins of serum into or irradiation albumin and α, β and γ immunoglobulins secondary polycythaemia poly- by electrophoresis (Fig. 67) (see also cythaemia secondary to another disease Fig. 66) or an environmental factor SET a gene, Set translocation, myeloid secretor an individual who has ABH leukaemia-associated, gene map locus antigens in saliva and other body fluids as 9q34.3, encodes a SET domain protein; a result of expression of the Se allele of SET contributes to the SET-CAN fusion the FUT2 gene; secretors are SeSe or gene formed by fusion of two genes at 9q34 Sese whereas non-secretors are sese; in rare cases of acute myeloid leukaemia non-secretors cannot synthesize Leb SET domain a highly conserved protein antigen (see FUT1) motif implicated in the modulation of HAE-S 01/13/2005 05:15PM Page 206

206 severe combined immunodeﬁciency (SCID)

Figure 67 Serum protein electrophoresis. Serum protein electrophoresis in a control normal sample (lane 1) and in nine patients with a paraprotein (lanes 2–10). The normal sample shows, from above down, albumin and α1, α2, β1, β2 (faint) and γ globulins. The nine patients’ samples show a paraprotein with mobility ranging from early to late γ; generally there is also a reduction of normal polyclonal immunoglobulins.

chromatin structure; originally identiﬁed sexually transmitted disease (STD) a Drosophila Su(var)3-9, ‘Enhancer of zeste’ disease transmitted by sexual intercourse, and Trithorax proteins; a signature of a venereal disease proteins that regulate the remodelling Sézary cell a neoplastic T lymphocyte of either transcriptionally active or re- with a characteristic convoluted or cere- pressed chromatin briform nucleus, present in the blood severe combined immunodeﬁciency in Sézary syndrome and sometimes in (SCID) a heterogeneous group of dis- mycosis fungoides orders leading to a severe defect in humoral Sézary syndrome a cutaneous T-cell and cell-mediated immunity, usually with lymphoma with circulating Sézary an autosomal recessive inheritance but cells sometimes showing an X-linked reces- SH-2 domain a protein motif found in cell sive inheritance; some of the underlying surface and intracellular signal-transducing defects are tabulated (Table 16) proteins which allows binding to phospho- severe congenital neutropenia a tyrosine-containing target proteins in a genetically heterogeneous group of con- phosphorylation-dependent manner ditions in which there is a severe con- SH2DIA a gene, also known as SAP, genital reduction in the neutrophil count, gene map locus Xq25, encoding SLAM- Kostmann’s syndrome associated protein (SAP); mutation leads sex chromatin the chromatin mass that to the X-linked lymphoproliferative syn- represents the inactive X chromosome, drome (see also CDISO) present as a drumstick-shaped append- SH3GL1 see EEN age in some granulocytes SHIP a gene, SH2-containing Inositol sex chromosomes the X and Y chro- Phosphatase, gene map locus 2q36-q37, mosomes; normal females have two X encoding an enzyme involved in phospho- chromosomes and normal males an X inositide turnover; it has a major role in and a Y chromosome negative signalling in lymphocytes and in sex-linked recessive a mode of inherit- the down-regulation of cytokine receptor- ance in which a gene on an X chromo- mediated signals in myeloid cells some leads to a disease or an inherited Shwachman–Diamond syndrome or characteristic in hemizygous males or Shwachman syndrome an inherited homozygous females (Fig. 68) disorder characterized by neutropenia, HAE-S 01/13/2005 05:15PM Page 207

Table 16 Some of the genetic causes of severe combined immunodeﬁciency.

Defect Inheritance Presence of T, B and NK cells

Deficiency of Janus-associated Autosomal recessive, JAK3 T−B+NK− kinase 3 gene at 19p13.1 Deficiency of common γ chain X-linked recessive, gene at T−B+NK− of receptors for IL-2, IL-4, IL-7, Xq13.1 IL-9 and IL 15 Deficiency of α chain of IL-7 Autosomal recessive, gene at T−B+NK+ receptor 5p13 Deficiency of β chain of IL-15 Autosomal recessive T−B+NK− receptor Adenosine deaminase deficiency Autosomal recessive, T−B−NK− mutation in the adenosine deaminase gene at 20q13.2- q13.11 Deficiencies of recombinase Autosomal recessive, RAG1 T−B−NK+ activating gene products and RAG2 genes at 6q21.3 Signalling defect Autosomal recessive, T+B+NK+ mutation in p56lck gene encoding a tyrosine kinase signalling molecule CD45 deficiency Autosomal recessive, T+B+NK+ mutation in gene for CD45 tyrosine phosphatase

Figure 68 Sex-linked recessive inheritance. The transmission of haemophilia through the female line from Queen Victoria to her descendants. It will be seen that transmission occurs from carrier females to haemophiliac males and that known carrier females are the children of either haemophiliac males or carrier females.

Normal male Female, either normal or of unknown carrier status Haemophiliac male Obligate carrier female HAE-S 01/13/2005 05:15PM Page 208

208 SI units

Figure 69 A sickle cell. of biological systems; dormant STATs A scanning electron micrograph of a sickle cell. exist in cytoplasmic multiprotein complexes; following ligand binding, receptor phosphorylation, either due to the action of Janus kinases (JAKs) or due to inherent receptor tyrosine kinase activity, allows docking of STATs to the receptor; this leads to STAT phosphorylation by JAKs; phosphorylated STATs are able to dimerize and are translocated to the nucleus where they can regulate gene expression by binding to STAT-responsive enhancers single-strand conformation polymor- exocrine pancreatic insufficiency and phism analysis (SSCP) a method of dyschondroplasia detection of mutations in which a single SI units units of the Système strand of DNA, a PCR product, is radio- International d’Unités labelled and subjected to non-denaturing sickle cell an erythrocyte that becomes gel electrophoresis; mobility depends sickle or crescent-shaped as a result of on conformation as well as size so that polymerization of haemoglobin S (Fig. 69) a single base substitution may alter the sickle cell anaemia the disease resulting mobility, permitting the recognition of from homozygosity for the βS gene an abnormality sickle cell disease a heterogene- sinusoid a thin-walled relatively large ous group of diseases, including sickle bone marrow vessel through which blood cell anaemia and various compound cells enter the circulation heterozygous states, in which clinico- SLC4A1 an alternative name for the AE1 pathological effects occur as a result of gene encoding band 3 of the red cell sickle cell formation membrane and the antigens of the Diego sickle cell trait heterozygosity for the βS blood group system gene SLC19A2 a gene at 1q23.2-23.3 encod- sideline a cytogenetic term for a daugh- ing a high-affinity thiamine transporter; ter clone identifiable because it shows mutation in this gene is responsible for karyotypic evolution thiamine-responsive megaloblastic anaemia sideroblast an erythroblast containing SLE systemic lupus erythematosus siderotic granules Sm expressed on the surface membrane sideroblastic anaemia an inherited of a cell, e.g. SmIg, surface membrane or acquired anaemia with the bone immunoglobulin marrow having a significant proportion small cell carcinoma of the lung a of ring sideroblasts neuroendocrine tumour of the lung siderocyte an erythrocyte containing small lymphocytic lymphoma a low siderotic granules grade lymphoma with neoplastic cells siderotic granule an iron-containing that resemble those of chronic lympho- granule that is identifiable by a Perls’ cytic leukaemia both cytologically and stain immunophenotypically sign a disease feature that is visible, smear cell a cell that has been crushed palpable or otherwise identifiable on during spreading of a blood film physical examination (cf. symptom) SMMHC a gene, Smooth Muscle Myosin Signal Transduction and Activator Heavy Chain gene, an alternative name of Transcription (STAT) proteins a for MYH11 family of at least 7 multi-domain tran- smooth endoplasmic reticulum scription factors that are activated in endoplasmic reticulum that lacks granules response to ligand signalling in a variety and therefore appears smooth; the smooth HAE-S 01/13/2005 05:15PM Page 209

splicing 209

endoplasmic reticulum serves to trans- size-fractionation by gel electrophore- port proteins from the rough endoplas- sis, then ‘blotting’ onto a nitrocellulose mic reticulum to the Golgi apparatus; the membrane; single-stranded DNA on the smooth endoplasmic reticulum of some membrane is hybridized to a comple- cells contains enzymes and can synthesize mentary sequence of single-stranded lipids DNA that serves as a probe SNX sorting nexins specific granule neutrophilic, eosino- solute a substance that is dissolved in philic and basophilic granules another substance specificity the capacity of a test to detect solvent a liquid in which something is an abnormality without giving positive dissolved results in the absence of an abnormality somatic cell any body cell except a germ spectrin an erythrocyte membrane pro- cell tein composed of dimers, tetramers and somatic hypermutation the process higher polymers of α spectrin and β spec- by which germinal centre B cells that have trin, encoded respectively by the SPTA1 been exposed to antigens undergo somatic and SPTB genes mutation so that they produce antibodies spermatozoon (plural spermatozoa) with a higher affinity for the relevant a germ cell produced in the testis of a male antigen; the cells producing the highest spheroacanthocyte a spherical cell with affinity antibodies are selected to survive, a small number of irregularly disposed a process known a affinity selection (see spicules clonal selection) spherocyte a spherical or near-spherical somatic mutation a mutation occurr- erythrocyte ing in a somatic cell, i.e. in any cell except spherocytosis the presence of spherocytes a germ cell; somatic mutation is a physio- sphingomyelin lipidosis Niemann– logical process in lymphoid cells but in Pick disease, an inherited disorder of lymphoid and other cells certain somatic metabolism in which there is a deficiency mutations can lead to the occurrence of of sphingomyelinase malignant disease spiculated cell a cell with spicules, e.g. somatic reversion correction of genetic an acanthocyte, echinocyte, keratocyte or defect in a clone of cells by a back muta- schistocyte tion, mitotic recombination or by a sec- spicule (i) an elongated projection from ond site mutation that alters the reading an erythrocyte (ii) a narrow piece of bone frame or leads to synthesis of a protein spleen a lymphoid organ which is also that is better tolerated than the original part of the reticuloendothelial system one splenectomy surgical removal of the SOP standard operating procedure spleen sorting nexins (SNX) a family of PX splenic pertaining to the spleen domain-containing intracellular molecules splenic atrophy regression of the spleen involved in the intracellular trafficking of splenic lymphoma with villous lym- endocytosed proteins phocytes a low grade B-cell neoplasm South-east Asian ovalocytosis an which, in the WHO classification, is inherited abnormality of the erythrocyte included in the category splenic marginal membrane leading, in heterozygotes, to zone lymphoma the presence of macro-ovalocytes and splenic marginal zone lymphoma a stomatocytes, resulting from mutation in low grade B-cell lymphoma the AE1 (band 3) gene splenic sequestration acute pooling Southern blotting a method, named of erythrocytes in the spleen in sickle cell from its inventor (Professor Ed South- disease ern), of identifying specific sequences of splenomegaly splenic enlargement DNA by means of cleaving the molecule splicing the process by which RNA with a restriction enzyme, followed by sequences, corresponding to introns in the HAE-S 01/13/2005 05:15PM Page 210

210 sprue

Figure 70 Staging of Hodgkin’s disease. A diagram showing the lymph node regions, as deﬁned for the staging of Hodgkin’s disease. Staging is carried out as shown in Table 17.

Cervical, supraclavicular, Waldeyer's ring pre-auricular, occipital

Infraclavicular Mediastinal

Axillary and pectoral Hilar

Epitrochlear Spleen Para-aortic Mesenteric

Inguinal and Iliac femoral

Popliteal

gene, are removed during processing of cellular mRNAs; contributed to a SRP20- RNA (see Fig. 65, p. 202) BCL6 fusion gene in a patient with trans- sprue a malabsorption syndrome formed follicular lymphoma SPTA1 the gene at 1q21 encoding α spec- SSCP single-strand conformation poly- trin, a component of the red cell mem- morphism analysis brane; mutation can result in hereditary ssp abbreviation for species, as in spherocytosis or hereditary elliptocytosis Candida ssp SPTB the gene at 14q22-q23.2 encoding β stab cell a band form or non-segmented spectrin, a component of the red cell mem- neutrophil brane; mutation can result in hereditary stage an expression of the extent of a spherocytosis or hereditary elliptocytosis malignant disease spur cell anaemia haemolytic anaemia staging the process by which the stage with acanthocytes occurring in severe of a disease is determined (Fig. 70 and liver disease Table 17) squamous cell carcinoma a malignant standard deviation (SD) a mathemat- tumour of epithelial cells ical indication of the degree of dispersion SRP20 a gene, SR Protein 20, gene map of values around a mean locus 6p21, encodes an adaptor protein standard error of the mean the mean kinase of the SR (Serine-Arginine) family divided by the square root of the number that is involved in the nuclear export of of observations HAE-S 01/13/2005 05:15PM Page 211

storage diseases 211

Table 17 Staging of Hodgkin’s disease (Hodgkin lymphoma). Each patient is given a composite stage e.g. IA. IIIB.

Stage Criteria

I Disease in one lymph node region (see Fig. 70) or lymphoid structure (e.g. thymus,

spleen or Waldeyer’s ring); stage IE has limited contiguous extension beyond a lymph node but with this being encompassable in a radiotherapy field II Disease in two or more lymph node regions or structures but confined to one side of the diaphragm III Disease on both sides of the diaphragm but confined to lymph nodes and lymphoid structures IV Spread (other than limited contiguous extension) beyond lymph nodes and spleen, e.g. to liver, lung or bone marrow A Having no B symptoms B Having (i) loss of more than 10% of body weight in the preceding 6 months (ii) drenching night sweats (iii) fever

standard operating procedure (SOP) stem cell transplantation transplanta- a codified description of the procedure tion of stem cells harvested either from for performing a laboratory test the bone marrow or from the peripheral ‘starry sky’ a histological appearance in blood Burkitt’s lymphoma and other high grade stem line a cytogenetic term for the neoplasms in which macrophages are seen parent clone from which other karyotyp- as pale areas in a background of small ically distinguishable daughter clones or dark neoplastic cells sidelines are derived STAT proteins see Signal Transduction sternal pertaining to the sternum and Activator of Transcription (STAT) sternum the breast bone, used for bone proteins marrow aspiration STAT5b a gene, Signal Transduction STL a gene, Six Twelve Leukaemia gene, and Activator of Transcription 5b, gene gene map locus 6q23, encodes a very map locus 17q11.2, encoding a STAT small protein with no known homologies; protein which acts downstream of growth STL contributed to an ETV6-STL fusion hormone, IL3 and IL5 signalling; con- gene in a B-lineage acute lymphoblastic tributed to a STAT5b-RARA fusion gene leukaemia cell line with t(6;12)(q23;p13) in a case of M1 acute myeloid leukaemia stochastic randomly determined statistical significance a statement of stoichiometric a reaction in which react- the probability that an apparent differ- ants combine with each other in a fixed ence or apparent relationship has arisen ratio, relating to their molecular weights by chance, expressed as a P value; a P value stomatitis inflammation of the mouth of < 0.01 indicates that the likelihood of a stomatocyte an erythrocyte with a slit- chance result is less than 1 in 100 shaped opening (see Fig. 43, p. 125) STD sexually transmitted disease stomatocytosis the presence of stem cell a cell capable of both replacing stomatocytes itself and giving rise to progeny storage cell a cell that has an increased stem cell factor (SCF) the ligand for content of a metabolite and appears to c-KIT, a growth factor for haemopoietic be storing it, e.g. a Gaucher’s cell or a stem cells and a regulator of mast cell dif- foamy macrophage ferentiation and function, encoded by the storage diseases inherited metabolic SCF gene at 12q22-24 disorders in which normal cell metabo- HAE-S 01/13/2005 05:15PM Page 212

212 stress polycythaemia

lites, which cannot be processed further Figure 71 Surface area nomogram. because of a metabolic block, accumulate A nomogram showing how surface area in cells and appear to be ‘stored’ can be estimated from the height and weight stress polycythaemia see pseudopoly- of a patient. This permits drug doses to be cythaemia calculated according to surface area. The stroma the connective tissue supporting surface area is more relevant than the an organ such as the bone marrow weight alone to the effect of a certain dose stromal pertaining to the stroma of a drug. structural proteomics the determina- Height Body surface Weight tion of structures of proteins that can m2 lb kg only be defined in the context of their 8" 160 interactions with other proteins, polynu- 200 2.9 340 6'6" 2.8 150 cleotides, lipids or carbohydrates 320 subacute combined degeneration of 4" 2.7 140 190 2.6 300 the spinal cord (SACD) degenera- 2" 130 2.5 280 tion of the posterior and lateral columns 6'0" 2.4 260 120 of the spinal cord as a consequence of 180 2.3 vitamin B deficiency 10" 240 110 12 2.2 105 Sudan black B a cytochemical stain 8" 170 2.1 220 100 which is taken up by the granules of 5'6" 95 myeloid cells 165 2.0 200 90 4" 190 sulphaemoglobin haemoglobin which 160 1.9 85 180 has been irreversibly oxidized by drugs 2" 1.8 80 155 170 or chemicals with incorporation of a 75 5'0" 1.7 160 sulphur atom into the porphyrin ring 150 70 suppressor cell a T cell that can sup- 10" 1.6 150 145 65 press the activities of B cells, cytotoxic T 140 8" 1.5 60 cells and helper T cells 140 130 supravital stain a stain performed on 4'6" 1.4 120 55 living, unfixed cells 135 4" 1.3 110 50 surface area an estimation of the total 130 area of the body covered by skin, can be 2" 100 1.2 45 derived from a height and weight nomo- 125 gram (Fig. 71), used for calculation of 4'0" 90 1.1 40 doses of anti-cancer drugs and for deter- 120 mining if an estimate of red cell mass and 10" 80 115 35 plasma volume is normal 1.0 survival curve a graphical representa- 8" 70 110 30 tion of the number of patients still alive 0.9 plotted against time 3'6" 105 60 Sweet’s syndrome acute neutrophilic dermatitis, can be a feature of acute 4" 0.8 25 myeloid leukaemia and the myelodysplas- 100 50 tic syndromes 2" SYK a gene, Spleen tyrosine Kinase, gene 95 0.7 20 map locus 9q22, encoding a non-receptor 3'0" tyrosine kinase; SYK contributed to a 90 40 ETV6-SYK fusion gene in a patient with 0.6 a myeloproliferative–myelodysplastic 2'10" 0.58 syndrome; loss of SYK expression in 85 15 breast cancer correlates with increased tumour load and invasiveness HAE-S 01/13/2005 05:15PM Page 213

systemic mastocytosis 213

symptom a feature of a disease that is systemic lupus erythematosus a experienced by the patient (cf. sign) multi-system autoimmune disease which syngeneic genetically identical, e.g. an may cause autoimmune haemolytic anaemia, identical twin autoimmune thrombocytopenic purpura and syntenic of genes, thought to be on a the development of antiphospholipid anti- single chromosome because they are bodies, including the ‘lupus anticoagulant’, lost concurrently with a speciﬁc marker associated with acquired thrombophilia gene that is known to be located on systemic mastocytosis a disseminated that chromosome mast cell neoplasm HAE-T 01/13/2005 05:16PM Page 214

T an abbreviation for the pyrimidine, delta), the notch protein is cleaved to gen- thymine erate an intracellular protein (notch-IC) TAL1 a gene, T-cell Acute lymphocytic which activate the RAS signalling path- Leukaemia 1, also known as Stem Cell way; Notch1 is truncated and loses its Leukaemia haemopoietic transcription extracellular domain in T-lineage acute factor, SCL, gene map locus 1p32, encodes lymphoblastic leukaemia associated with a basic helix–loop–helix transcription t(7;9)(q34;q34); removal of the Notch factor that is essential for haemopoiesis extracellular domain results in a domin- and vasculogenesis; forms transcription- ant gain-of-function Notch allele ally active heterodimers with any of the TCF3 see E2A isoforms encoded by the E2A locus; its TAM transient abnormal myelopoiesis normal activity is regulated by interac- t-AML therapy-related acute myeloid tion with CBP and LIM domain proteins; leukaemia TAL1 is dysregulated: TAP1 and TAP2 Transporter-associated • by a small deletion, detectable only by with Antigen Processing genes that encode molecular techniques, which fuses most proteins delivering peptides to develop- of the gene with the promoter of the ing HLA type I molecules; mutation of upstream SIL (SCL Interrupting Locus) either gene can result in an immune gene, associated with T-lineage acute deficiency syndrome (see bare lymphocyte lymphoblastic leukaemia syndrome and HLA type I deficiency) • by proximity to the TCRAD (αδ) Taq-Man™ a semi-quantitative PCR locus at 14q11 in T-lineage acute lym- technique incorporating a target- phoblastic leukaemia associated with sequence-specific fluorescent probe as t(1;14)(p32;q11) well as the necessary primers; the probe is • by proximity to the TCRB gene at labelled with two fluorescent dyes, a 7q35 in T-lineage acute lymphoblastic reporter and a quencher; during the PCR, leukaemia associated with t(1;7)(p32;q35) the exonuclease activity of Taq poly- TAL2 a gene, T-cell Acute lymphocytic merase destroys the probe and releases Leukaemia 2, gene map locus 7q35, the reporter dye, which fluoresces; the encodes a homologue of TAL1 that is level of fluorescence reflects the amount essential for embryonic brain develop- of product generated, which is in turn ment; dysregulated by proximity to the dependent upon the amount of starting TCRB gene at 7q35 in T-lineage acute material (see Fig. 63, p. 197) lymphoblastic leukaemia associated with Taq polymerase a heat-stable DNA t(7;9)(q35;p13) polymerase that is used for PCR TAN1 a gene, Translocation-Associated target cell an erythrocyte with haemo- Notch homologue 1 (Notch1), gene map globin concentrated in the centre of the locus 9q34, encodes a transmembrane cell, giving the appearance of a target receptor homologue of the Drosophila tartrate-resistant acid phosphatase notch protein; when notch proteins (TRAP) an enzyme present in hairy cells bind their ligands, (known as jagged and and occasionally in cells of other types

214 HAE-T 01/13/2005 05:16PM Page 215

telomerase 215

of non-Hodgkin’s lymphoma; also ex- TCL1b see TCL1a pressed by osteoclasts TCL3 see HOX11 TAX the transforming protein encoded TCL6 see TCL1a by human T-cell leukaemia virus type I TCR T-cell receptor (HTLV-I); constitutively activates NFκB TCRAD (αδ) the T-Cell Receptor Alpha (see also REL) by binding to and chronic- Delta (αδ) locus, gene map locus 14q11, ally activating IκB kinase (IκK), an where there are a cluster of genes encod- enzyme complex that phosphorylates and ing the alpha and delta chains of the T- inactivates IκB, thereby allowing NFκB cell receptor; the TCRA genes have V to enter the nucleus (variable), J (joining) and C (constant) TBI total body irradiation gene segments; the TCRD genes have V T cell a T lymphocyte (variable), D (diversity), J (joining) and C T-cell receptor surface membrane (constant) gene segments; the TCRAD receptors in T cells; they are of two types, locus contributes to oncogenesis by lead- αβ and γδ; T cells with an αβ T-cell re- ing to the dysregulation of proto-onco- ceptor are capable of recognizing and genes which are brought into proximity binding an antigen-derived peptide in the to it, a relatively common mechanism context of an autologous MHC (HLA- of leukaemogenesis in T-lineage acute encoded) complex on the surface of an lymphoblastic leukaemia antigen-presenting cell; different T-cell TCRB the T-Cell Receptor Beta gene, gene receptor molecules recognize preferent- map locus 7q35, where there are a cluster ially peptides in an HLA class I (with of genes encoding the beta chain of the up-regulation of CD8 then occurring) T-cell receptor; there are V (variable), D or class II context (with up-regulation (diversity), J (joining) and C (constant) of CD4 then occurring) gene segments; the TCRB locus con- T chronic lymphocytic leukaemia a tributes to oncogenesis by leading to the term which has been variously used to dysregulation of proto-oncogenes which designate large granular lymphocyte are brought into proximity to it; a rela- leukaemia, T prolymphocytic leukaemia tively common mechanism of leukaemo- and other entities; to avoid ambiguity, genesis in T-lineage acute lymphoblastic the use of this term is not recommended leukaemia TCL1a T-Cell Leukaemia/lymphoma 1a, TCRG the T-Cell Receptor Gamma locus gene map locus 14q32.1, encodes a coact- on chromosome 7 where there are a ivator of the AKT kinase which is nor- cluster of genes encoding the gamma mally expressed in primitive B and T chain of the T-cell receptor; there are V lymphocytes; TCL1 is dysregulated in (variable), J (joining) and C (constant) inv(14)(q11q32) and t(14;14)(q11;q32) gene segments associated with T-cell prolymphocytic TdT terminal deoxynucleotidyl transferase leukaemia; the dysregulation is conse- teardrop poikilocyte a teardrop quent on the gene being brought into shaped erythrocyte, particularly a feature proximity to the TCRAD (αδ) locus at of myeloﬁbrosis and of megaloblastic 14q11; in addition to TCL1a, three other anaemia genes normally expressed in primitive TEL see ETV6 lymphoid cells and overexpressed in telangiectasia permanent dilation of 14q32.1 rearrangements are present at superﬁcial capillaries and venules of the this locus: TCL1b (T Cell Leukaemia/ skin or the mucous membrane which can lymphoma 1b) encoding a homologue lead to haemorrhage of TCL1a; TNG1 (TCL1-Neighbouring telomerase an RNA-protein complex Gene-1) and TNG2 (TCL1-Neighbour- that is essential for maintaining nucleo- ing Gene-2) which encode proteins of protein caps at the telomeres; it is com- unknown function; TNG1 and TNG2 are posed of telomerase RNA (hTR) and a sometimes collectively referred to as TCL6 specialized reverse transcriptase (hTERT) HAE-T 01/13/2005 05:16PM Page 216

216 telomere

telomere one of the two ends of a domain of TFG fused to the tyrosine chromosome kinase domain of ALK and are oligo- telophase the final stage of mitosis in merized leading to constitutive tyrosine which the chromosomes assemble at kinase activity the two poles of the cell where they are TFR2 a gene at 7q22 encoding a transfer- surrounded by a nuclear membrane, rin receptor, mutation of which leads to following which the cytoplasm begins to a small minority of cases of hereditary divide (see Fig. 6, p. 14) haemochromatosis TEM transmission electron microscopy TFRC the gene encoding the major trans- temporal arteritis inflammation of the ferrin receptor superficial temporal artery, usually asso- TGFβ transforming growth factor β ciated with a high erythrocyte sedimenta- TGFB a gene, gene map locus 19q13.1, tion rate, can cause blindness encoding Transforming Growth Factor teniposide an anti-cancer drug which Beta; germ line mutations in TGFB interacts with topoisomerase-II are the cause of Camurati–Engelmann teratogen a substance that can cause disease, an autosomal dominant disorder fetal malformation when administered characterized by skeletal defects to a pregnant woman, e.g. coumarin Th1 a subset of helper T cells (type 1 anticoagulants helper T cells) that secrete interleukin-2, terminal deoxynucleotidyl trans- interferon-γ and lymphotoxin (tumour ferase (TdT) a DNA polymerase necrosis factor β) and promote cellular that catalyses terminal incorporation immune responses of nucleotides into DNA, a marker of Th2 a subset of helper T cells (type 2 immature cells of lymphoid and, to a helper T cells) that secrete interleukin-4, lesser extent, myeloid lineages interleukin-5 and interleukin-6 and pro- termination codon also known as a mote B-cell proliferation and antibody stop codon, a codon that causes termina- secretion tion of protein synthesis thalassaemia an inherited disorder in tetramer a polymer composed of four which one of the component chains of monomers haemoglobin is synthesized at a reduced tetraploid having 92 chromosomes rate tetraploidy the presence of two sets of thalassaemia intermedia a thalas- chromosomes in a cell so that there are saemic condition that is moderately 92 chromosomes severe but nevertheless does not require TF the gene encoding transferrin; muta- regular transfusions to sustain life tions leading to atransferrinaemia cause thalassaemia major thalassaemia microcytic anaemia with iron overload; a that is incompatible with more than a common polymorphism among Euro- short survival in the absence of blood pean populations leads to a slight reduc- transfusion tion in serum transferrin concentration thalassaemia minor an asymptomatic and predisposes menstruating woman to thalassaemic condition iron deficiency anaemia therapeutic of benefit in treatment of a TFG a gene, TRK-Fused Gene, also disease known as TRKT3, gene map locus therapy treatment 3q11-q12, encodes a ubiquitously ex- therapy-related acute myeloid pressed coiled-coil protein of uncertain leukaemia (t-AML) acute myeloid function which normally exists as multi- leukaemia following the use of mutagenic mers; TFG contributes to one of two drugs or radiotherapy and likely to be TFG-ALK fusion genes in occasional aetiologically related to such therapy cases of anaplastic large cell lymphoma therapy-related myelodysplastic syn- associated with t(2;3)(p23;q21); the chi- drome (t-MDS) a myelodysplastic maeric proteins carry the coiled-coil syndrome following the use of mutagenic HAE-T 01/13/2005 05:16PM Page 217

tissue plasminogen activator (tPA) 217

drugs or radiotherapy and likely to be tissue factor activity, and incomplete aetiologically related to such therapy thromboplastins, which can act as a thiamine-responsive megaloblastic platelet substitute in the intrinsic pathway anaemia a constitutional disorder with of coagulation autosomal recessive inheritance, charac- thrombopoietin (TPO) a hormone that terized by sensorineural deafness, diabetes promotes thrombopoiesis mellitus and thiamine-responsive mega- thrombosis the process of formation of loblastic anaemia with ring sideroblasts, a blood clot resulting from mutation in the SLC19A2 thrombotic thrombocytopenic pur- gene pura (TTP) a consumptive coagulopathy thrombasthenia a severe inherited leading to thrombocytopenic purpura, defect in platelet function characterized by a clinical pentad of thrombin the activated form of pro- fever, neurological abnormalities, throm- thrombin that converts fibrinogen into bocytopenia, microangiopathic haemolytic fibrin (see Figs 17 and 18, pp. 77 and 78) anaemia and renal impairment thrombin time (TT) the time needed thrombus (plural thrombi) a blood for plasma to clot after the addition of clot within a blood vessel thrombin, a test for fibrinogen concentra- thrush candidiasis, usually of the mouth tion and function and for the presence of or vagina, a common condition in thrombin inhibitors such as heparin immunosuppressed patients thrombocythaemia an increased thymic pertaining to the thymus platelet count thymine a nitrogenous base that pairs thrombocytopenia a reduced platelet with adenine (a pyrimidine) count thymocyte a lymphoid cell in the thymus thrombocytopenic purpura subcuta- thymoma a tumour of the thymus, can neous bleeding caused by a low platelet be associated with pure red cell aplasia count thymus a lymphoid organ in the medi- thrombocytosis an increased platelet astinum, important in the development of count T-lineage lymphocytes thromboembolism deep vein thrombo- TIF2 a gene, Transcriptional Intermedi- sis and pulmonary embolism ary Factor 2, gene map locus 8q13, thrombolysis lysis of a clot encodes a transcriptional activator which thrombolytic therapy administration normally binds to CBP; TIF2 contributes of a drug, e.g. streptokinase, in order to to the MOZ-TIF2 fusion gene in acute cause lysis of a clot myeloid leukaemia associated with thrombomodulin an endothelial cell inv(8)(p11q13) surface glycoprotein that interacts with tinzaparin a low molecular weight heparin thrombin to activate protein C; deficiency, tissue an organized arrangement of cells which is very rare, is associated with an tissue factor altered or damaged tissue increased risk of thrombosis that is able to activate the extrinsic path- thrombophilia an increased propensity way of coagulation; may also be secreted to form thrombi, either arterial or venous by activated monocytes thrombophlebitis inflammation of tissue factor pathway inhibitor a veins lipoprotein-associated inhibitor of the thrombophlebitis migrans venous factors VIIa and Xa; also know as ex- thrombosis recurring over a short period trinsic pathway inhibitor; the majority is of time at multiple sites, often indicative bound to endothelial cells with the min- of underlying carcinoma ority being in the plasma (see Fig. 56, thromboplastin a substance that pro- p. 170) motes blood clotting; thromboplastins tissue plasminogen activator (tPA) a used in the laboratory are divided into substance secreted by various tissues that complete thromboplastins, which have is able to convert plasminogen to plasmin HAE-T 01/13/2005 05:16PM Page 218

218 TLI

Figure 72 T cell development (opposite). A diagrammatic representation of the development of T lymphocytes. The common lymphoid progenitor in the bone marrow gives rise to precursor T lymphoblasts, which traverse the blood stream as naïve CD4-negative CD8-negative T-cell precursors. After entering the cortex of the thymus, T-cell receptor genes (TCR) are rearranged and CD4 and CD8 are expressed. The thymocytes then undergoes positive selection, as a result of presentation of antigen-derived peptides by cortical epithelial cells; peptides presented are either endogenous peptides in an MHC class I context or exogenous peptides in an MHC class II context leading the thymocytes to express, respectively, CD8 alone or CD4 alone. The thymocytes then undergo negative selection with apoptosis of self-reactive cells occurring. Following presentation of the relevant antigen by an antigen-presenting cell, such as a dendritic cell or a macrophage, thymocytes mature into a T cells with cytotoxic or helper potential. These lymphocytes traverse the blood stream and enter lymphoid tissues where they may be presented with either processed endogenous antigen (e.g. derived from a tumour cell or a virus-infected cell) in an MHC class I context or processed exogenous antigen in an MHC class II context. Antigen-presenting cells are macrophages, dendritic cells or B cells, the latter having trapped antigen by means of surface membrane receptors. The CD8- positive T cells, if presented with endogenous antigen in the correct context, develop into cytotoxic effector T cells which can migrate to other tissues and cause apoptosis of cells bearing the antigen. The CD4-positive helper precursor (Th0) cells, if presented with antigen in an appropriate context, develop into one of two types of helper cell, either Th1 helper cells, which help cytotoxic T cells, activate NK cells and macrophages and mediate inﬂammatory responses, or Th2 helper cells which help B cells, promote eosinophil production and can mediate allergy. Both types of helper cell secrete cytokines which create a positive feedback loop, thus enhancing the speciﬁc type of helper response. In addition, interferon-γ secreted by Th1 cells suppresses Th2 cells and IL4 secreted by Th2 cells suppresses Th1 cells.

TLI total lymphoid irradiation TOP1 the DNA Topoisomerase I gene, T lineage pertaining to T lymphocytes gene map locus 20q11, which contributes and their precursors to a NUP98-TOP1 fusion gene in therapy- TLS see FUS induced acute myeloid leukaemia or T lymphocyte (i) a lymphocyte that is myelodysplastic syndrome associated capable of participating in cell-mediated with t(11;20)(p15;q11) (see also topoiso- immunity following antigen binding or merase I) (ii) an abnormal cell related to normal T TOP2A the DNA Topoisomerase IIα lymphocytes (Fig. 72) gene, gene map locus 17q21-q22, that TNF tumour necrosis factor may be ampliﬁed in acute myeloid leuk- TNFα tumour necrosis factor α aemia; point mutations in this gene TNF-receptor-associated periodic syn- have been observed in leukaemic cell lines drome a dominantly inherited syn- resistant to amsacrine (see also topoiso- drome resulting from a mutation in the merase II) type 1 tumour necrosis factor receptor topoisomerase an enzyme that makes gene, leading to periodic fever, myalgia a transient break in a strand of DNA and erythema associated with neutro- topoisomerase I an enzyme that makes philia and an acute phase response a transient break in a single strand of TNFRSF6 the gene, previously known as DNA APT1, that encodes fas (CD95), a protein topoisomerase II an enzyme that makes important in lymphocyte apoptosis; a transient double-stranded break in a mutation of TNFRSF6 leads to the auto- strand of DNA immune lymphoproliferative syndrome topoisomerase II-interactive drugs TNFSFS6 the gene encoding fas ligand, also known as topoisomerase II inhi- mutations of which underlie some cases bitors, anti-cancer drugs that act by inter- of the autoimmune lymphoproliferative fering with the action of topoisomerase syndrome gene (type Ib) II; they can also result in myelodysplastic tolerance reduced ability to mount an syndromes or acute myeloid leukaemia immune response to speciﬁc antigens total body irradiation (TBI) irradiation toluidine blue a metachromatic stain of the whole body, may be used as prepar- for identifying basophils and mast cells ation for bone marrow transplantation HAE-T 01/13/2005 05:16PM Page 219

toxic granulation 219

Bone marrow Peripheral blood Precursor T lymphoblast

Naive T cell CD4– CD8– thymocyte CD4+ CD8+ TCR+ thymocyte

Cortical Positive selection Cortical epithelial cell epithelial cell Thymic presenting presenting cortex self-peptide exogenous peptide in MHC-class I in MHC-class II context context

CD8+ CD4– CD8– CD4+ thymocyte thymocyte

Negative selection (apoptosis of self-reactive cells)

Dendritic Dendritic Thymic cell or cell or medulla macrophage macrophage

CD8+ CD4+ cytotoxic helper Peripheral Tc Th0 blood T cell T cell

CD8+ CD4+ Stimulation cytotoxic Tc Th0 helper of cytotoxic T cell T cell T cells Lymphoid Activation tissue CD4+ IL2 of NK cells Antigen- CD4+ γ Th1 IFN and presenting B cell, B CD8+ Tc macrophages macrophage cytotoxic Th0 or dendritic cell T cell CD4+ presenting B IL4 Class endogenous Antigen- Th2 IL5 switching antigen in presenting IL6 IL10 MHC class I Effectors B cells, macrophages Eosinophilia context cytotoxic T cell or dendritic cells —causes apoptosis present exogenous of cells bearing antigen in MHC antigen class II context

total iron-binding capacity the total total parenteral nutrition (TPN) capacity of serum or plasma to bind and administration of all known necessary transport iron nutrients intravenously total lymphoid irradiation (TLI) irra- toxic granulation increased staining of diation of all major lymphoid organs, neutrophil granules occurring as a response may be used as preparation for bone to infection and inﬂammation but also as marrow transplantation a physiological change during pregnancy HAE-T 01/13/2005 05:16PM Page 220

220 toxoplasmosis

toxoplasmosis disease resulting from sists of the oligomerization domains infection by Toxoplasma gondii, a of TPM3 fused to the tyrosine kinase protozoan parasite; may cause lym- moiety of ALK which is constitutively phadenopathy and atypical lymphocytes activated TP53 a gene, Tumour Protein p53, TPM4 a gene, Tropomyosin 4, gene map gene map locus 17p13, encoding p53, locus 19p13 that contributed to a TPM4- a transcription factor that is normally ALK fusion gene in a case of anaplastic expressed only in actively dividing cells large cell lymphoma with NK phenotype but which is very abundant in most trans- associated with t(2;19)(p23;p13) formed cells; p53 functions as a homo- TPN total parenteral nutrition tetrameric transcription factor which TPO the gene at 3q27-28, encoding activates many genes ﬂanked by a p53 thrombopoietin binding site, whilst repressing other genes TPO thrombopoietin that do not have such a site; induced by T prolymphocytic leukaemia (T-PLL) DNA damaging agents, high levels of a chronic leukaemia of T lineage with normal p53 lead to cell cycle arrest or characteristic clinical, haematological and apoptosis; p53 up-regulates WAF, thus cytogenetic characteristics inhibiting cyclin–cyclin-dependent kinase trabecula (plural trabeculae) a complexes, arresting the cell cycle and spicule of bone permitting repair of damaged DNA; TRALI transfusion-related acute lung injury in addition, p53 up-regulates BAX, thus trans having an effect on a gene on promoting apoptosis; an archetypal another chromosome tumour suppressor gene, germline muta- transcobalamin a plasma protein that tions in one allele of TP53 are seen in the binds to, and transports, cobalamin

Li–Fraumeni syndrome (which shows (vitamin B12); transcobalamins I and II an increased incidence of acute myeloid are synthesized by neutrophils and leukaemia); TP53 mutation occurs as a transcobalamin II by hepatocytes second event in many haematological transcript an RNA molecule, corres- neoplasms, being implicated in poor ponding to one gene, transcribed from prognosis myelodysplastic syndromes, nuclear DNA transformation of chronic granulo- transcription the synthesis of RNA on a cytic leukaemia (20–30%), progression DNA template (Fig. 73) or transformation of lymphoproliferat- transcription factor a protein that ive disorders, e.g. chronic lymphocytic binds to specific enhancer sequences and leukaemia (c. 15%) and Richter’s syn- also to RNA polymerase and thus regu- drome (c. 40%), Burkitt’s lymphoma, lates transcription of specific genes acute myeloid leukaemia (40–50%), transduction the transfer of a bacterial Hodgkin’s disease (60–80%), adult T- gene from one bacterium to another by a cell leukaemia/lymphoma (c. 24%) and bacteriophage some cases of multiple myeloma; hemizy- transfection the in vitro introduction of gously lost in acute lymphoblastic DNA into cells leukaemia with 17p– transferrin a plasma protein that trans- tPA tissue plasminogen activator ports iron T-PLL T prolymphocytic leukaemia transfer RNA (tRNA) RNA molecules TPM3 a gene, Tropomyosin 3, gene that bind to specific amino acids and map locus 1q25 encoding non-muscular transport them to ribosomes for incorpor- tropomyosin, a ubiquitously expressed ation into peptide chains actin-binding protein; TPM3 contri- transformation (i) the process by which butes to a TPM3-ALK fusion gene in a normal cell develops the phenotypic t(1;2)(q25;p23), a variant translocation characteristics of a malignant or neoplastic associated with anaplastic large cell cell (ii) evolution of a low grade to a high lymphoma; the chimaeric protein con- grade neoplasm HAE-T 01/13/2005 05:16PM Page 221

transgene 221

Figure 73 Transcription. Transcription of RNA requires the presence of regulatory proteins (RPs), RNA polymerase II (RPOLII), general transcription factors (GTFs) and mediator proteins. (a) RPOLII is a multi-subunit enzyme, which catalyses mRNA synthesis but is unable to recognize or bind promoter sequences itself. Instead it relies on GTFs, a group of accessory proteins, to recruit it to the transcriptional start site. Transcription is controlled by RPs which binding to enhancers. However RPOLII and GTFs alone cannot respond to RPs unless they bind to a multi-subunit complex of mediator proteins (M). The combination of M, GTFs and RPOLII constitutes the transcription initiation complex. (b and c) The serine-rich carboxy-terminal domain (CTD) of the largest subunit of RPOLII is unmodiﬁed during transcriptional initiation, but is progressively and massively phosphorylated (P) as transcription progresses. Phosphorylation allows the CTD to act as a scaffold for the sequential attachment of RNA processing machinery to the nascent transcript, i.e. the capping enzymes (C), the spliceosome (S) and the cleavage/polyadenylation enzymes (X). Initial phosphorylation is by a GTF protein, TFIIH; subsequent phosphorylation is achieved by the recruitment of the kinase p-TEFb by the capping enzymes.

(a) Nucleosome GTFs +/– RPOLII RP M

Enhancer TATA CTD Compacted Promoter chromatin Transcription initiation complex

(b) (c) RPOLII RPOLII

Promoter P P P P P P P P P P P

S X A C A RNA A A U A Intron A

transforming growth factor β (TGFβ) transforming virus a virus capable of a multifunctional protein, encoded by inducing malignant transformation of TGFB, gene map locus 19q31, that con- animal cells in culture trols proliferation, differentiation, and transfusion the introduction of blood or other functions in many cell types; it blood components into the bloodstream has no sequence homology with trans- transfusion-related acute lung injury forming growth factor α; secreted by (TRALI) acute lung damage follow- B cells, T cells, macrophages and mast ing shortly after blood transfusion, cells; cells which synthesize TGFβ have usually as a result on transfusion of speciﬁc receptors for it; TGFα and β blood containing high titre anti-leucocyte are classes of transforming growth fac- antibodies tors which act synergistically in inducing transgene a gene introduced into a germ transformation. cell, usually of another species HAE-T 01/13/2005 05:16PM Page 222

222 transgenic animal

Figure 74 Translation. Translation is the process by which the sequence of codons of a messenger RNA (mRNA) directs the synthesis of a polypeptide chain. The mRNA code is read in a 5′ to 3′ direction, directing protein synthesis in an amino- to carboxy- direction. It is a cytoplasmic event that takes place on large ribonucleoprotein complexes called ribosomes, which comprise large and small subunits. Amino acids enter the ribosome attached to transfer RNA (tRNA) molecules. Each tRNA is only able to recognize one amino acid (to which it is covalently linked) and contains a trinucleotide sequence (anticodon) complementary to the codon representing the amino acid that it carries. Translation starts at an initiation codon, which is usually AUG (encoding methionine). This codon is ﬂanked by certain consensus sequences in the 5′ untranslated region (UTR) of the mRNA that are complementary to the 3′ end of the ribosomal RNA in the small subunit; this ensures that all methionine codons do not act as translational start sites. The small subunit binds mRNA and guides the anticodon sequences of incoming tRNAs to the mRNA codon currently being translated. The large subunit catalyses the transfer of the carboxy end of the nascent polypeptide chain, which is attached to the tRNA bound to the preceding codon, to the amino end of the amino acid attached to the incoming tRNA. Translational initiation and elongation are dependent upon GTPase accessory factors (initiation and release factors). Translational termination begins when a stop codon is encountered. Release factors cleave the polypeptide from the tRNA at the last coding codon and ribosome recycling factors lead to the dissociation of ribosomes.

5'GpppN AAAAAAn mRNA GTP AUG CCA AGG GTP UAG UAC GGU UCC Codon GDP GDP

Anticodon

Initiation Elongation Termination

Nascent polypeptide

Large ribosomal subunit Small ribosomal subunit Amino acid

tRNA Exon Initiation factor Release factors

Untranslated region Elongation factor Ribosome recycling proteins

transgenic animal an animal, usually a translation the synthesis of protein from mouse, expressing a gene of another a mRNA template (Fig. 74) species, which is introduced by injecting translocation the transfer of part of a DNA containing the required gene into chromosome to another chromosome; the pronucleus of a fertilized egg may be reciprocal or non-reciprocal, bal- transient abnormal myelopoiesis anced or unbalanced (Fig. 75) (TAM) a transient leukaemia occurring transmission electron microscopy in neonates with Down’s syndrome (TEM) an electron microscopy tech- HAE-T 01/13/2005 05:16PM Page 223

tumour necrosis factor α (TNFα) 223

Figure 75 Translocation. triploidy the presence of an extra copy of A translocation is a transfer of part of one each chromosome in a cell so that there chromosome to another; most often this is are a total of 69 chromosomes reciprocal. This figure contrasts an inversion of trisomy the presence of three rather than chromosome 3 with five translocations involving the same chromosome: (a) inv(3)(q21q26); two copies of a chromosome in a cell or (b) t(3;3)(q21;q26); (c) t(1;3)(p36;q21); clone (d) t(3;5)(q21;q31); t(3;12)(q26;p13); trisomy 21 (i) Down’s syndrome (ii) the t(3;21)(q26;q22). presence of an extra copy of chromosome 21 in a cell, a clone of cells or an individual TRKC a gene, Tyrosine Kinase receptor 3, also known as Neurotrophic Tyrosine Kinase receptor 3, NTRK3, gene map locus 15q25, encoding a receptor tyrosine kinase, that contributes to a ETV6-TRKC fusion gene in acute myeloid leukaemia associated with t(12;15)(p13;q25); the chimaeric protein is a constitutively activated tyrosine kinase tRNA transfer RNA tropical spastic paraparesis (TSP) a myelopathy caused by HTLV-I, the retrovirus which also causes adult T-cell leukaemia/lymphoma tropical splenomegaly see hyperreactive malarial splenomegaly TSP tropical spastic paraparesis TTF a gene, RhoH/TTF- Translocation Three Four, also known as RAS Homo- logue gene family member H (ARHH), gene map locus 4p13, encoding a haemo- nique in which electrons pass through a poietic-cell-specific small GTPase of the thin section of a cell or tissue, revealing Rho subfamily of RAS-like molecules; is its internal structure (see Figs 12 and 14, involved in cytoskeletal organization; the pp. 29 and 31) gene contributes to the TTF-BCL6 fusion transplant tissue or cells deliberately gene in B-lineage non-Hodgkin’s lym- transferred to another individual with the phoma associated with t(3;4)(q27;p13) intention of achieving engraftment and was rearranged to the IGH locus transplantation the introduction into in one case of multiple myeloma with the body of viable cells from another indi- t(4;14)(p13;q32) vidual with the intention of achieving TTP thrombotic thrombocytopenic purpura engraftment tuberculosis a disease resulting from TRAP tartrate-resistant acid phosphatase infection by Mycobacterium tuberculosis trephine a strong needle for performing tumour a solid mass of tissue, usually a biopsy of bone and bone marrow neoplastic in nature trephine biopsy (i) the procedure by tumour necrosis factor α (TNFα) an which a biopsy specimen of bone and bone acute phase reactant, a cytokine secreted marrow is obtained, using a trephine (ii) by macrophages, NK cells, T lympho- jargon for a biopsy specimen obtained with cytes, B lymphocytes and mast cells, which a trephine promotes inflammation, encoded by a trilineage involving the granulocyte– gene at 6p21.3; a monoclonal antibody to monocyte, erythroid and megakaryocyte TNFα, infliximab, is available for thera- lineages peutic use HAE-T 01/13/2005 05:16PM Page 224

224 tumour necrosis factor β

tumour necrosis factor β see lympho- interferon-γ and lymphocytotoxin (tumour cytotoxin necrosis factor β) but not interleukin-4, tumour suppressor gene a normal interleukin-5 or interleukin-6; it is mainly cellular gene, one of a subset of proto- responsible for activation of macrophages oncogenes, which helps to control growth and for T-cell mediated cytotoxicity and proliferation of cells; the loss of func- type 2 (Th2) helper T cell a CD4+ tion of tumour suppressor gene can con- helper T cell that secretes interleukin-4, tribute to either the development or the interleukin-5, interleukin-6, interleukin-9, progression of a neoplastic tumour interleukin-10 and interleukin-13 but not type 1 blast a blast cell with no granules interleukin-2 or interferon; it is mainly (FAB group definition) responsible for helping B cells type 2 blast a blast cell with scanty gran- tyrosine kinase a generic term indic- ules but without features of a promyelo- ating an enzyme capable of catalysing cyte such as a lower nucleocytoplasmic the phosphorylation of tyrosine residues ratio, an eccentric nucleus and a Golgi in proteins; they are usually template zone (FAB group definition) specific; tyrosine kinases may be surface type 1 (Th1) helper T cell a CD4+ membrane receptors or cytoplasmic and helper T cell that secretes interleukin-2, function in signal transduction HAE-U 01/13/2005 05:16PM Page 225

U an abbreviation for the pyrimidine, unbalanced translocation a trans- uracil location in which there has been net gain ubiquitin a small globular protein which or loss of part of one or both involved exists throughout the cell (hence its chromosomes (Fig. 76) name), either in a free form or conjugated unconjugated bilirubin bilirubin that to other proteins through a covalent has not been conjugated to glucuronic bond between the glycine at its carboxy acid by the liver; an increased concentra- terminal end and the side chains of lysine tion of unconjugated bilirubin occurs in on other proteins; encoded as either lin- haemolytic anaemia ear repeats (polyubiquitin) or fused to a unfractionated heparin heparin as ribosomal protein gene—after protein extracted from animal tissues, with synthesis, the enzyme ubiquitin C- molecular weights ranging from 5000 to terminal hydrolase liberates individual 30 000 daltons protein units universal donor a blood donor whose ubiquitination the post-translational blood can be transfused into patients of modification process whereby ubiquitin is any blood group, i.e. an O Rh D-negative conjugated to target protein; the process donor (without a high titre of anti-A or involves the sequential actions of activ- anti-B antibodies) ating (E1), conjugating (E2), and ligase universal precautions an approach (E3) enzymes; E3 proteins carry RING to prevention of transmission of blood- fingers and bind specific substrates through borne pathogens by regarding every a structural motif known as a ubiquitina- blood sample as potentially high risk tion signal (degron); monoubiquitina- universal recipient a recipient of a tion targets proteins for endocytosis and blood transfusion who can receive blood nascent proteins for secretion; polyubiq- of any group, i.e. an AB Rh D-positive uitination marks proteins for destruction individual in proteasomes Upshaw–Schulman syndrome a UGT1 the gene encoding UDP glu- recessively inherited syndrome of recur- curonosyl Transferase-1, a polymorphism rent thrombocytopenia and microangio- in the promoter of which causes Gilbert’s pathic haemolytic anaemia resulting syndrome from deficiency of von Willebrand factor- UKCCG United Kingdom Cancer cleaving protein Cytogenetics Group uracil a pyrimidine that pairs with adenine ultrasonography imaging parts of the uraemia the presence in the blood of body by means of sound waves of such excessive amounts or urea and other a high frequency that they are inaudible nitrogenous compounds as a result of to the human ear renal failure ultrasound very high frequency sound urobilinogen a breakdown product of ultrastructure the features of a cell as bilirubin, present in the faeces and urine ascertained by means of an electron URO-D the gene encoding URoporphy- microscope rinogen Decarboxylase, mutation of which

225 HAE-U 01/13/2005 05:16PM Page 226

226 urokinase

Figure 76 Unbalanced translocation. causes about a third of cases of familial Most translocations are balanced, i.e. there is no loss porphyria cutanea tarda of chromosomal material detectable by standard urokinase a thrombolytic compound cytogenetic analysis. However there are some present in the urine translocations that are often unbalanced. One such is t(1;19)(q23;p13), observed in B-lineage acute urticaria pigmentosa cutaneous mas- lymphoblastic leukaemia. It can occur as a balanced tocytosis translocation (a) or as an unbalanced translocation USP25 a gene, Ubiquitin-Speciﬁc Pro- (b). In the unbalanced translocation, designated tease 25, gene map locus 21q11, encodes a der(19)t(1;19)(q23;p13) the derivative chromosome 1 deubiquitinating enzyme which cleaves (comprising a large part of chromosome 1 and a free ubiquitin from ubiquitin precursors small contribution from the short arm of chromosome 19) is lost and is replaced by a second and ubiquitinylated proteins; USP25 copy of the normal chromosome 1. The derivative contributes to an AML1-USP25 fusion chromosome 19 is not lost. Effectively there is gene, encoding a truncated AML1 pro- monosomy for a small part of 19p (which is lost with tein, in myelodysplastic syndromes the der(1)) and triploidy for a large part of 1p, which is present in the two copies of a normal chromosome 1 and also in the der(19).

Normal Derivative Normal Derivative 1 1 19 19 (a) Balanced translocation t(1;19)(q23;p13)

Normal Duplicated Normal Derivative 1 normal 19 19 1 (b) Unbalanced translocation der(19)t(1;19)(q23;p13) HAE-V 01/13/2005 05:17PM Page 227

vacuole a fluid-filled cavity within a cell causes Chuvash polycythaemia and other which, in the case of phagocytes, is formed rare familial polycythaemias, probably by invagination of the surface membrane because impaired degradation of HIP1α variable expressivity a variation in the leads to enhanced synthesis of erythropoi- expression of a phenotype between indi- etin; there is also enhanced synthesis of viduals with the same genotype (in con- transferrin and transferrin receptor trast to penetrance, which is an all or none vimentin an antigen expressed by rhab- phenomenon) domyosarcoma, Ewing’s sarcoma and variable number of tandem repeats spindle cell carcinoma (VNTR) a variable number of copies of vinblastine a plant alkaloid used in a DNA sequence at a specific locus that treating leukaemia, lymphoma and some can be used as a genetic marker solid tumours variance a number representing the vinca alkaloids alkaloids derived from dispersion of measured values around a plants of the Vinca genus, used as mean expressed as SD2 chemotherapeutic agents, e.g. vincristine, varicella-zoster a herpesvirus that vinblastine, vindesine causes chicken pox (varicella) and shin- vincristine a plant alkaloid used in treat- gles (herpes zoster) ing leukaemia, lymphoma and some solid vasculitis inflammation of blood vessels tumours vegan an individual who eats no animal vindesine a plant alkaloid used in treat-

protein; veganism can cause vitamin B12 ing leukaemia, lymphoma and some solid deficiency tumours vegetarian an individual who abstains viral pertaining to a virus from the flesh of animals and may or may viral haemorrhagic fever one of a not eat fish, eggs and milk group of viral infections causing fever vein a thin-walled vessel conducting and haemorrhage (which is consequent blood back to the heart on consumption of platelets), e.g. Lassa venepuncture the puncturing of a vein fever and Ebola fever in order to obtain a blood sample virus a very small micro-organism, not venereal pertaining to or caused by visible with a light microscope and cap- sexual intercourse able of replicating only within a living venous pertaining to veins plant or animal cell venous thromboembolism deep vein viscera the internal organs thrombosis and pulmonary embolism visceral pertaining to a viscus venule a small thin-walled vessel con- viscosity the capacity of a fluid to flow ducting blood towards the heart, con- more or less readily necting capillaries and veins viscus an internal organ VHL the gene encoding Von Hippel Lindau vital stain a stain applied to living cells protein, which targets hypoxia-inducible vitamin B6 pyridoxine, a vitamin which protein 1α (HIP1α) for degradation; homo- may be useful in some cases of sideroblas- zygosity for a mutation in this gene tic anaemia

227 HAE-V 01/13/2005 05:17PM Page 228

228 vitamin B12

Table 18 Characteristics of subtypes of type 2 von Willebrand’s disease.

Ristocetin-induced Factor-VIII Subtype of 2 HMW multimers platelet aggregation binding capacity

2A Absent Decreased Normal 2B* Reduced/absent Increased Normal 2M Normal Decreased Normal 2N† Normal Normal Markedly reduced

* May have thrombocytopenia. † Disease in homozygotes and compound heterozygotes for 2 A and 2 N types of mutation.

vitamin B12 a vitamin essential for con- platelet-type von Willebrand’s disease), version of homocysteine to methionine classified as: and for conversion of methylmalonyl • type I, quantitative, partial deficiency, CoA to succinyl CoA autosomal dominant vitamin B12 deficiency an insuffici- • type 2, qualitative, functional ency of vitamin B12, potentially leading deficiency, mainly autosomal dominant to megaloblastic anaemia, peripheral (Table 18) neuropathy, subacute degeneration of the • type 3, quantitative, complete spinal cord, optic atrophy and dementia deficiency, autosomal recessive (disease vitamin D a vitamin essential for the in compound heterozygotes or homozy- normal absorption of calcium gotes) vitamin K a vitamin which is essential for von Willebrand’s factor a coagulation synthesis of the coagulation factors, fac- factor and adhesion molecule, encoded tor II, factor VII, factor IX and factor X, by the VWF gene, produced by endothe- and of the naturally occurring anticoagu- lial cells and megakaryocytes: it is a car- lants, protein C and protein S rier protein for factor VIII and is also vitamin K antagonist an orally act- necessary for normal platelet–endothelial ive anticoagulant that antagonizes the cell interactions through its binding, action of vitamin K by interfering with γ- predominantly, to platelet glycoprotein carboxylation of precursors of vitamin-K Ib/IX dependent proteins von Willebrand’s factor-cleaving pro- vitiligo acquired patchy depigmenta- tease a metalloproteinase encoded by tion of the skin; there is an association an ADAMTS family gene, ADAMTS13, between pernicious anaemia and vitiligo at 9q34, which causes limited proteolysis VNTR variable number of tandem repeats of large multimers of von Willebrand’s volunteer unrelated donor (VUD) a factor released from endothelial cells; bone marrow or haemopoietic stem cell inherited or acquired deficiency can cause donor who is unrelated to the recipient thrombotic thrombocytopenic purpura but has been matched for histocompati- VWF the gene at 12p13.3 that encodes von bility antigens Willebrand’s factor, mutation of which von Willebrand’s disease a hae- can lead to autosomal dominant or auto- morrhagic disorder consequent of von somal recessive von Willebrand’s disease Willebrand’s factor deficiency (see also VUD volunteer unrelated donor HAE-W 01/13/2005 05:17PM Page 229

WAF1 an alternative name for CDKN1A whole chromosome painting a tech- the gene encoding p21WAF, a protein that nique for identifying individual chromo- negatively regulates the cell cycle; WAF is somes by the use of a combination of up-regulated by the tumour suppressor probes that bind with a high level of spec- gene, TP53 ificity to a single pair of chromosomes Waldenström’s macroglobulinaemia whooping cough pertussis; the dis- a disease consequent on a lymphoplas- ease caused by infection by Bordetella macytoid lymphoma with secretion of pertussis an IgM paraprotein, the latter leading to wild type gene the normal form of a hyperviscosity gene, in contrast to a mutant gene Waldeyer’s ring the ring of lymphoid Wilson’s disease an inherited meta- tissue, including the tonsils, encircling bolic disorder resulting from mutations the pharynx in the copper transporting ATPase, warfarin one of the coumarin ATP7B, leading to overloading of tissues anticoagulants with copper; haemolytic anaemia may WASp a gene at Xp11.22-11.23, mutation occur as a presenting feature of late in the of which is responsible for the Wiskott– course of the disease Aldrich syndrome and X-linked thrombo- Wiskott–Aldrich syndrome a syn- cytopenia in some families and, rarely, drome of thrombocytopenia, eczema severe congenital neutropenia and immune deficiency, resulting from WBC white blood cell count, white cell mutation in the WASp gene count wnt a family of evolutionarily conserved Western blot a modification of the genes which encode secreted glycopro- Southern blot, used for identification of teins homologous to Drosophila wingless; proteins; the name is a play on words their cognate receptors are members of Whipple’s disease a malabsorption the fz (frizzled) family of transmembrane syndrome resulting from infection by molecules; intracellular signalling is Tropheryma whippelii mediated via a variety of proteins white cell a leucocyte—a granulocyte, including beta catenin monocyte or lymphocyte Wolfram syndrome a syndrome white cell count a quantification of the resulting from mutation of the WFS1/ number of white cells in a defined volume wolframin gene, gene map locus 4p16.1; of blood WFS1 encodes a widely expressed endo- WHO World Health Organization plasmic reticulum membrane protein; WHO classification a comprehensive wolfram syndrome is characterized by classification of haematological neo- diabetes insipidus, diabetes mellitus, plasms published in its definitive form in optic atrophy and deafness (DID- 2001, see Tables 2, 4, 6, 7 and 10–14 and MOAD); some patients also have sider- Fig. 55, pp. 7, 8, 127, 129, 137, 153, 157, oblastic anaemia and deletions of 167 and 168, respectively mitochondrial genes

229 HAE-W 01/13/2005 05:17PM Page 230

230 Wolman’s disease

Wolman’s disease an inherited meta- forms; in addition is known to bind RNA bolic disorder, a juvenile form of choles- and may form part of the spliceosome terol ester storage disease (see Fig. 65, p. 202); a candidate tumour Working Formulation a lymphoma suppressor gene, mutation of which is classification which was superseded by the associated with an increased incidence of REAL and then the WHO classifications Wilms’ tumour (and an increased incid- World Health Organization (WHO) ence of acute myeloid leukaemia follow- an international organization for the ing Wilms’ tumour and in relatives of improvement of world health, source of patients with Wilms’ tumour); encodes a the WHO classification of tumours of transcription factor involved in growth haemopoietic and lymphoid tissues and differentiation of various normal woven bone young bone which has not and neoplastic cells; expressed in normal yet been organized into a lamellar structure CD34+ haemopoietic progenitor cells Wright’s stain a Romanowsky stain and overexpressed in CD34+ cells in which is the predominant stain used in acute myeloid leukaemia and chronic the USA and Canada granulocytic leukaemia; expressed in WT1 a gene, Wilms Tumour 1 gene, gene blast cells of 88% of cases of acute lym- map locus 11p13, encodes a zinc finger phoblastic leukaemia and 97% of cases of transcription factor existing in four iso- acute myeloid leukaemia. HAE-X 01/13/2005 05:17PM Page 231

X the X chromosome, of which one copy kinase which is required for B lympho- is found in normal males and two copies cyte development in normal females X-linked lymphoproliferative disease xanthoma a subcutaneous nodule or an inherited susceptibility to severe dis- plaque containing cholesterol ease following primary EBV infection, xenograft a graft (transplant) from one resulting from a mutation in the SAP species to another gene (Signalling Lymphocyte Activation xerocytosis an inherited defect of the Molecule (SLAM)-associated protein) at erythrocyte membrane leading to increased Xq25, also known as SH2D1A, which cation flux, dehydration of cells and encodes a NK and T-lymphocyte surface haemolytic anaemia membrane protein that is part of the sig- XG a gene at Xpter-22.32 encoding the nalling pathway when these cells interact Xga blood group antigen with virus-infected B cells; SAP on T cells XK a locus at Xp21.1-21.1 where there is a interacts with SLAM (CD150) on both gene encoding Kx, a protein linked to the T cells and B cells and also with 2B4 Kell blood group antigens; lack of Kx (CD244) on NK cells leads to the McLeod phenotype X-linked sideroblastic anaemia an X inactivation the inactivation of one of inherited sideroblastic anaemia resulting two copies of X chromosome genes in from mutation in the erythroid-specific somatic cells of females (see Lyon hypoth- δ-amino laevulinic acid synthase gene, esis and Lyonization) ALAS2; the condition mainly affects X-linked pertaining to characteristics or males but can occur in females as a result diseases transmitted by genes on the X of skewed X chromosome inactivation chromosome, includes X-linked domin- X-rays gamma irradiation, electromag- ant and X-linked recessive; sex-linked is netic radiation of shorter wave length synonymous than visible light that is able to penetrate X-linked agammaglobulinaemia a many tissues thus permitting the produc- congenital X-linked deficiency in humoral tion of an image of a part of the body, immunity resulting from a mutation in applied therapeutically to destroy malig- the BTK, the gene encoding Bruton’s nant tissues Tyrosine Kinase, a cytoplasmic tyrosine

231 HAE-Y 01/13/2005 05:17PM Page 232

Y the Y chromosome, found in males but sequences complementary to human not in normal females DNA sequences serve as a probe for YAC yeast artiﬁcial chromosome those sequences yeast artiﬁcial chromosome (YAC) yellow marrow fatty bone marrow yeast chromosomes that can incorporate (cf. red marrow) large segments of foreign DNA, used in yolk sac part of an embryo, the initial recombinant DNA technology; DNA site of formation of blood cells

232 HAE-Z 01/13/2005 05:17PM Page 233

ζ the Greek letter, zeta; one of the two zinc finger a metal-binding protein chains of haemoglobin Gower 1 and motif that allows nucleic acid (DNA and haemoglobin Portland RNA) binding and which is a key com- ZAP70 Zeta chain Associated Protein ponent of many transcription factors; kinase 70, also known as SRK (Syk- there are estimated to be up to 800 zinc Related tyrosine Kinase), gene map locus finger containing proteins in the human 2q12, encodes a nonreceptor tyrosine genome kinase expressed in T and NK cells which ZNF198 a gene, Zinc Finger protein 198, associates with the TCR zeta chain and is also known as Rearranged in Atypical phosphorylated upon antigen stimula- Myeloproliferative disorder (RAMP) and tion; several germline mutations in this Fused In Myeloproliferative disorders gene have been observed in kindreds with (FIM); gene map locus 13q12, encodes a severe T-cell immunodeficiency (NK and zinc finger protein; ZNF198 contributes B cells are normal) to a ZNF198-FGFR1 fusion gene in a zidovudine a drug used in the treatment syndrome of chronic myelomonocytic of AIDS which can cause megaloblastic leukaemia with eosinophilia/T-lineage anaemia and pancytopenia lymphoblastic lymphoma (the 8p11 Ziehl–Neelsen a stain for Mycobacteria, syndrome); the fusion protein comprises which are acid-fast with this stain the amino-terminal domains of ZNF198 Zieve’s syndrome acute haemolytic fused to tyrosine kinase FGFR1 and is anaemia with hyperlipidaemia occurring in constitutively activated patients with acute alcoholic liver disease zygote a fertilized ovum

233