DOCSLIB.ORG

Prognostic Biomarkers in Myelodysplastic Syndromes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Prognostic Biomarkers in Myelodysplastic Syndromes Myelodysplastic syndromes Prognostic biomarkers in myelodysplastic syndromes M. Cazzola ABSTRACT Prognostic biomarkers in myelodysplastic syndromes (MDS) include cytogenetic abnormalities and Department of Hematology somatic gene mutations. Recurrent chromosomal abnormalities are found in approximately 50% of Oncology, Fondazione Istituto cases, and are mainly secondary genetic events. By contrast, somatic oncogenic mutations, responsible di Ricovero e Cura a Carattere for disease pathogenesis and progression, are found in up to 90% of MDS patients. Oncogenic muta - Scientifico (IRCCS) Policlinico tions can be classified as: i) founding or initiating driver mutations, which cause a selective advantage San Matteo, and Department in a hematopoietic cell with capacity for self-renewal and lead to formation of a clone of mutated of Molecular Medicine, myelodysplastic cells; ii) subclonal or cooperating driver mutations, which occur in cells of an already University of Pavia, Pavia, Italy established clone and generate subclones carrying both the founding and the newly acquired muta - tion. Driver mutant genes include those of RNA splicing, DNA methylation, histone modification, tran - Correspondence: Mario Cazzola scription regulation, DNA repair, signal transduction, and cohesin complex. Only 6 genes ( TET2, SF3B1, E-mail: [email protected] ASXL1, SRSF2, DNMT3A , and RUNX1 ) are consistently mutated in 10% or more of MDS patients, while Acknowledgments: a long tail of additional genes are mutated less frequently. Reliable genotype/phenotype relationships The studies on the genetic basis of have already been established, primarily the close association between SF3B1 mutation and ring sider - myeloid neoplasms conducted at the oblasts. Clonal and subclonal mutations appear to affect prognosis equally, and outcome correlates Department of Hematology with the number of driver mutations. Ongoing studies aim to develop molecular models for clinical Oncology, Fondazione IRCCS decision-making. Policlinico San Matteo, and the Learning goals Department of Molecular Medicine, University of Pavia, Italy, were sup - At the conclusion of this activity, participants should be able to: ported by grants from the - describe driver somatic mutations in myelodysplastic syndromes, including the main biological Associazione Italiana per la Ricerca pathways involved; sul Cancro (AIRC), Fondazione - explain the difference between founding and subclonal mutations; Cariplo, MIUR (PRIN 2010-2011), - describe at least an established genotype:phenotype relationship in myelodysplastic syndromes; and FIRB (project n. RBAP11CZLK). -describe the diagnostic and prognostic relevance of somatic mutations in myelodysplastic syndromes. Hematology Education: the education program for the annual congress of the European Introduction ized by cytopenia, myelodysplasia, ineffective Hematology Association hematopoiesis, and increased risk of progres - sion to acute myeloid leukemia (AML). 3 The 2014;8:237-242 Diagnostic and prognostic biomarkers in current diagnostic approach to MDS includes myelodysplastic syndromes (MDS) have been peripheral blood and bone marrow morpholo - recently analyzed in this Education Program 1 gy to evaluate abnormalities of peripheral by Hellström-Lindberg. In the present paper, I blood cells and hematopoietic precursors, will focus on genetic biomarkers. We have bone marrow biopsy to assess marrow cellu - recently reviewed the genetic basis of MDS 2 larity and fibrosis, and cytogenetics to identify and its clinical relevance in Blood. The reader non-random chromosomal abnormalities. 4 is, therefore, referred to this open access Based on these parameters, MDS are currently review article for more detailed information categorized according to the 2008 World (http://bloodjournal.hematologylibrary.org/co Health Organization (WHO) classification, ntent/122/25/4021.long), while the present which is reported in Table 1. As shown in paper summarizes the crucial points only. As Figure 1, the current WHO classification of such, the present paper must be considered an MDS has valuable prognostic relevance. acceptable secondary publication intended to disseminate important information to the widest possible audience, in agreement with Pathophysiology of myelodysplastic the criteria of the International Committee of syndromes Medical Journal Editors (ICMJE, http://www. icmje.org/publishing_d.html). Our working model of the pathophysiology of MDS is reported in Figure 2. As demon - strated by Walter et al. 5 through studies of Classification of myelodysplastic whole genome sequencing, the vast majority syndromes of myeloid precursors (i.e. immature red cells, granulocytic/monocytic precursors, and Myelodysplastic syndromes are clonal megakaryocytes) are clonally derived in MDS. hematopoietic stem cell disorders character - The myelodysplastic clone originates from the Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 237 | 19 th Congress of the European Hematology Association occurrence in an immature hematopoietic stem cell of a somatic mutation that provides survival and growth advantage: typically this founding mutation involves genes of RNA splicing or DNA methylation. 2 During the natural course of the disease, the acquisition of additional driver mutations leads to formation of subclones of hematopoietic cells with further impaired differentiation and/or maturation capacity: the proportion of blast cells progressively increases over time, and overt AML eventu - ally develops. Recurrent chromosomal abnormalities in myelodys - plastic syndromes Recurrent chromosomal abnormalities are detected in approximately half of patients with MDS, 6 and the most common aberrations include del(5q), trisomy 8, del(20q), and monosomy 7 or del(7q). 6,7 While most of these abnor - malities are secondary genetic events, the isolated del(5q) of the 5q- syndrome represents a founding event, involv - ing haploinsufficiency for RPS14 and miR-145. 8-10 The recent study of 7012 patients aimed to develop the revised International Prognostic Scoring System (IPSS-R) for MDS has clearly demonstrated the prognostic rele - vance of chromosomal abnormalities with respect to sur - 11 vival and risk of evolution into AML. This cytogenetic Figure 1. Kaplan-Meier analysis of overall survival and risk classification has also been found to predict the out - leukemia-free survival of 1110 patients diagnosed with come of allogeneic hematopoietic stem cell transplanta - MDS at the Department of Hematology Oncology, 12 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, tion (HSCT) in MDS patients. In particular, patients with between 1990 and 2012. MDS patients are stratified monosomal karyotype, defined as the karyotype of according to the 2008 WHO classification categories. patients who had two (or more) autosomal monosomies or Multilineage dysplasia and excess of blasts have a consid - erable impact on outcomes. Reproduced from Cazzola et one monosomy in combination with other structural al. 2 abnormalities, have a very poor outcome. 12 Table 1. 2008 WHO classification of myelodysplastic syndromes (from Swerdlow et al. 3). MDS subtype Blood findings Bone marrow findings Refractory cytopenia Unicytopenia or bicytopenia, Unilineage dysplasia ( ≥10% of the cells in one myeloid lineage) <5% blasts, with unilineage dysplasia (RCUD) no or rare blasts (<1%) <15% ringed sideroblasts within erythroid precursors Refractory anemia with ringed Anemia, no blasts Erythroid dysplasia only, < 5% blasts, ≥15% ringed sideroblasts within erythroid precursors sideroblasts (RARS) Refractory cytopenia with Cytopenia(s), no or rare blasts Dysplasia in ≥10% of cells in 2 or more myeloid multilineage dysplasia (RCMD) (<1%), no Auer rods, cell lineages (erythroid precursors and/or neutrophil precursors and/or megakaryocytes), <1x10 9/L monocytes <5% blasts, no Auer rods (the percentage of ringed sideroblasts is irrelevant) Refractory anemia with Cytopenia(s), <5% blasts, no Unilineage or multilineage dysplasia, 5-9% blasts, no Auer roads excess blasts-1 (RAEB-1) Auer roads, <1x10 9/L monocytes Refractory anemia Cytopenia(s), 5-19% blasts, Unilineage or multilineage dysplasia, 10-19% blasts, occasional Auer rods with excess blasts-2 (RAEB-2) occasional Auer rods, <1x10 9/L monocytes Myelodysplastic syndrome associated Anemia, normal to increased Normal to increased megakaryocytes with hypolobated nuclei, <5% blasts, no Auer with isolated del(5q) platelet count, no or rare blasts rods, isolated del(5q) (<1%) Myelodysplastic syndrome, Cytopenia (various combinations), Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell lines when unclassifiable (MDS-U) no or rare blasts (<1%) accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS, <5% blasts | 238 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 Somatic gene mutations in myelodysplastic Diagnostic, prognostic and predictive significance syndromes of driver mutations, and development of molecular models for clinical decision-making Our understanding of the molecular basis of MDS has improved dramatically in the last four years as a result of 13-22 The identification of founding and subclonal driver a few fundamental studies. A list of the most common mutations has the potential to considerably improve diag - recurrently
Load more

Recommended publications
  • (NCCN Guidelines®) Myelodysplastic Syndromes Version 2.2018 — February 15, 2018
    NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Myelodysplastic Syndromes Version 2.2018 — February 15, 2018 NCCN.org NCCN Guidelines for Patients® available at www.nccn.org/patients Continue Version 2.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. NCCN Guidelines Version 2.2018 NCCN Guidelines Index Table of Contents Myelodysplastic Syndromes Discussion *Peter L. Greenberg, MD/Chair ‡ Þ Karin Gaensler, MD ‡ Lori J. Maness, MD ‡ Stanford Cancer Institute UCSF Helen Diller Family Fred & Pamela Buffett Cancer Center Comprehensive Cancer Center *Richard M. Stone, MD/Vice Chair ‡ † Margaret R. O’Donnell, MD ‡ Dana-Farber/Brigham and Women’s Guillermo Garcia-Manero, MD ‡ City of Hope Comprehensive Cancer Center Cancer Center The University of Texas MD Anderson Cancer Center Daniel A. Pollyea, MD Þ † ‡ Aref Al-Kali, MD ‡ University of Colorado Cancer Center Mayo Clinic Cancer Center Elizabeth A. Griffiths, MD Þ † ‡ Roswell Park Cancer Institute Vishnu V. Reddy, MD ≠ † John M. Bennett, MD Þ † ≠ University of Alabama at Birmingham Consultant David Head, MD ≠ Comprehensive Cancer Center Vanderbilt-Ingram Cancer Center Hetty Carraway, MD † ‡ Paul J. Shami, MD ‡ Case Comprehensive Cancer Center/University Ruth Horsfall, PhD, MSc ¥ Huntsman Cancer Institute Hospitals Seidman Cancer Center and Patient Advocate at the University of Utah Cleveland Clinic Taussig Cancer Institute Robert A. Johnson, MD † Alison R. Walker, MD ‡ Peter Curtin, MD† ‡ St. Jude Children’s Research Hospital/The University The Ohio State University Comprehensive UC San Diego Moores Cancer Center of Tennessee Health Science Center Cancer Center - James Cancer Hospital and Solove Research Institute Carlos M.
    [Show full text]
  • Minimal Morphological Criteria for Defining Bone Marrow
    Leukemia (2015) 29, 66–75 & 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes MG Della Porta1,2,13, E Travaglino1,13, E Boveri3,13, M Ponzoni4, L Malcovati1,5, E Papaemmanuil6, GM Rigolin7, C Pascutto1, G Croci3,5, U Gianelli8, R Milani4, I Ambaglio1, C Elena1, M Ubezio1,5, MC Da Via’1,5, E Bono1,5, D Pietra1, F Quaglia2, R Bastia2, V Ferretti1, A Cuneo7, E Morra9, PJ Campbell6,10,11, A Orazi12,RInvernizzi2,14 and M Cazzola1,5,14 on behalf of Rete Ematologica Lombarda (REL) clinical network The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (490%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34 þ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34 þ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS.
    [Show full text]
  • When Should We Think of Myelodysplasia Or Bone Marrow Failure in a Thrombocytopenic Patient? a Practical Approach to Diagnosis
    Journal of Clinical Medicine Review When Should We Think of Myelodysplasia or Bone Marrow Failure in a Thrombocytopenic Patient? A Practical Approach to Diagnosis Nicolas Bonadies 1,2,† , Alicia Rovó 1,† , Naomi Porret 1 and Ulrike Bacher 1,* 1 Department of Hematology and Central Hematology Laboratory, Inselspital Bern, University of Bern, 3010 Bern, Switzerland; [email protected] (N.B.); [email protected] (A.R.); [email protected] (N.P.) 2 Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland * Correspondence: [email protected]; Tel.: +41-31-632-1390; Fax: +41-31-632-3406 † Equal contribution. Abstract: Thrombocytopenia can arise from various conditions, including myelodysplastic syn- dromes (MDS) and bone marrow failure (BMF) syndromes. Meticulous assessment of the peripheral blood smear, identification of accompanying clinical conditions, and characterization of the clinical course are important for initial assessment of unexplained thrombocytopenia. Increased awareness is required to identify patients with suspected MDS or BMF, who are in need of further investigations by a step-wise approach. Bone marrow cytomorphology, histopathology, and cytogenetics are comple- mented by myeloid next-generation sequencing (NGS) panels. Such panels are helpful to distinguish reactive cytopenia from clonal conditions. MDS are caused by mutations in the hematopoietic Citation: Bonadies, N.; Rovó, A.; stem/progenitor cells, characterized by cytopenia and dysplasia, and an inherent risk of leukemic Porret, N.; Bacher, U. When Should progression. Aplastic anemia (AA), the most frequent acquired BMF, is immunologically driven and We Think of Myelodysplasia or Bone characterized by an empty bone marrow. Diagnosis remains challenging due to overlaps with other Marrow Failure in a hematological disorders.
    [Show full text]
  • Myeloproliferative Neoplasms - Clinical Merase Chain Reaction (PCR).The Patient Was Treated with Imatinib and Achieved Hematologic and Cytogenetic Remission
    Stockholm, Sweden, June 13 – 16, 2013 cific amplification of the genomic breakpoints and reverse transcription poly - Myeloproliferative neoplasms - Clinical merase chain reaction (PCR).The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L-PDGFRB B1556 mRNA or genomic DNA, confirming a long term molecular remission on ima - RECURRENT CEP85L-PDGFRB FUSION IN A PATIENT WITH A TRANSLO - tinib. In our view, the detection of the exact gene fusion is clinically relevant for CATION T(5;6) AND AN IMATINIB-RESPONSIVE MYELOPROLIFERATIVE effective long term management of these neoplasms as it enables specific fol - NEOPLASM WITH EOSINOPHILIA low up by sensitive molecular analysis. N Winkelmann 1,2* , C Hidalgo-Curtis 1,3, K Waghorn 1,3, J Score 1,3, H Dickin - son 4, A Jack 5, S Ali 6, N Cross 1,3 1Leukaemia Research Group , Wessex Regional Genetics Laboratory, Salis - B1557 bury, United Kingdom, 2Klinik für Innere Medizin II , Universitätsklinikum Jena, CLINICAL SIGNIFICANCE OF IMMATURE PLATELET FRACTION IN BCR- Jena, Germany, 3Faculty of Medicine, University of Southampton, Southamp - ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS ton, 4Cytogenetics Unit, St. James´s University Hospital, 5Haematological N Vazzana 1* , R Spadano 1, S Di Zacomo 2, G Rolandi 3, A Dragani 1 Malignancy Diagnostic Service, St James’s University Hospital, Leeds, 6Hull 1Department of Hematology, Centre for Hemophilia and Rare Blood Disorders, Royal Infirmary, Hull Royal Infirmary, Hull, United Kingdom 2Department of Transfusion Medicine, Molecular Biology Unit, 3Department of Transfusion Medicine, Coagulation Unit, Pescara, Italy Background: Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies Background: Platelet activation plays a pivotal role in the pathogenesis of and solid tumors.
    [Show full text]
  • Myelodysplastic Syndromes — Coping with Ineffective
    PERSPECTIVE Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis Mario Cazzola, M.D., and Luca Malcovati, M.D. Related article, page 549 One of the most challenging problems in hema- cytes. Families with an inherited genetic predispo- tology is the heterogeneous group of disorders sition and multistep progression to a myelodysplas- that were formally defined as myelodysplastic syn- tic syndrome and acute myeloid leukemia have been dromes by the French–American–British Coopera- reported1 but are extremely rare. Whether idiopath- tive Group in 1982. This set of disorders includes ic myelodysplastic syndromes are truly clonal pro- idiopathic conditions as well as the secondary or liferations of multipotent stem cells, however, is un- therapy-related forms that develop after exposure clear. The biologic hallmark of these stem cells in to alkylating agents, radiation, or both. Idiopathic myelodysplastic syndromes is, rather, a defective myelodysplastic syndromes occur mainly in older capacity for self-renewal and differentiation. The persons: the incidence of these syndromes is about consequences of this abnormality are probably am- 5 per 100,000 persons per year in the general pop- plified in the elderly because the aging process it- ulation, but it increases to 20 to 50 per 100,000 per- self may not only deplete stem cells, but also alter sons per year after 60 years of age. Approximate- the marrow microenvironment, particularly in per- ly 15,000 new cases are expected in the United sons with occupational or environmental exposure States each year, indicating that myelodysplastic to chemical and physical hazards. The resulting per- syndromes are at least as common as chronic lym- turbed interactions between hematopoietic progen- phocytic leukemia, the most prevalent form of leu- itors and marrow stromal cells are probably respon- kemia in Western countries.
    [Show full text]
  • Standardization of Flow Cytometry in Myelodysplastic Syndromes
    Leukemia (2012) 26, 1730 --1741 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu SPECIAL REPORT Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group TM Westers1, R Ireland2,24, W Kern3,24, C Alhan1, JS Balleisen4, P Bettelheim5, K Burbury6, M Cullen7, JA Cutler8, MG Della Porta9, AM Dra¨ger1, J Feuillard10, P Font11, U Germing4, D Haase12, U Johansson13, S Kordasti2, MR Loken8, L Malcovati9, JG te Marvelde14, S Matarraz15, T Milne2, B Moshaver16, GJ Mufti2, K Ogata17, A Orfao15, A Porwit18, K Psarra19, SJ Richards7, D Subira´ 20, V Tindell2, T Vallespi21, P Valent22, VHJ van der Velden14, TM de Witte16, DA Wells8, F Zettl12,MCBe´ne´ 23 and AA van de Loosdrecht1,24 Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as ‘normal’, ‘suggestive of’, or ‘diagnostic of’ MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced.
    [Show full text]
  • Mediterranean Journal Od Hematology and Infectious Diseases
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Mediterranean Journal of Hematology and Infectious Diseases Review article Diagnostic Utility of Flow Cytometry in Myelodysplastic Syndromes. Matteo G. Della Porta1 and Cristina Picone2 1 Cancer Center, Humanitas Research Hospital & Humanitas University, Rozzano – Milan, Italy. 2 Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia Italy. Competing interests: The authors have declared that no competing interests exist. Abstract. The pathological hallmark of myelodysplastic syndromes (MDS) is marrow dysplasia, which represents the basis of the WHO classification of these disorders. This classification provides clinicians with a useful tool for defining the different subtypes of MDS and individual prognosis. The WHO proposal has raised some concern regarding minimal diagnostic criteria particularly in patients with normal karyotype without robust morphological markers of dysplasia (such as ring sideroblasts or excess of blasts). Therefore, there is clearly need to refine the accuracy to detect marrow dysplasia. Flow cytometry (FCM) immunophenotyping has been proposed as a tool to improve the evaluation of marrow dysplasia. The rationale for the application of FCM in the diagnostic work up of MDS is that immunophenotyping is an accurate method for quantitative and qualitative evaluation of hematopoietic cells and that MDS have been found to have abnormal expression of several cellular antigens. To become applicable in clinical practice, FCM analysis should be based on parameters with sufficient specificity and sensitivity, data should be reproducible between different operators, and the results should be easily understood by clinicians. In this review, we discuss the most relevant progresses in detection of marrow dysplasia by FCM in MDS Keywords: Myelodysplastic Syndrome; Flow Cytometry; Diagnostic Tools.
    [Show full text]
  • Standardization of Flow Cytometry in Myelodysplastic Syndromes
    Leukemia (2012) 26, 1730 --1741 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu SPECIAL REPORT Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group TM Westers1, R Ireland2,24, W Kern3,24, C Alhan1, JS Balleisen4, P Bettelheim5, K Burbury6, M Cullen7, JA Cutler8, MG Della Porta9, AM Dra¨ger1, J Feuillard10, P Font11, U Germing4, D Haase12, U Johansson13, S Kordasti2, MR Loken8, L Malcovati9, JG te Marvelde14, S Matarraz15, T Milne2, B Moshaver16, GJ Mufti2, K Ogata17, A Orfao15, A Porwit18, K Psarra19, SJ Richards7, D Subira´ 20, V Tindell2, T Vallespi21, P Valent22, VHJ van der Velden14, TM de Witte16, DA Wells8, F Zettl12,MCBe´ne´ 23 and AA van de Loosdrecht1,24 Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as ‘normal’, ‘suggestive of’, or ‘diagnostic of’ MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced.
    [Show full text]
  • Myelodysplastic Syndromes
    ® HEMATOLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE Myelodysplastic Syndromes The Hospital Physician Hematology Board Review Manual is a study guide for fellows and practicing physicians preparing for board Contributors: examinations in hematology. Each manual Jasleen Randhawa, MD reviews a topic essential to the current prac­ tice of hematology. Mazie Froedtert Willms and Sue Froedtert Cancer Fellow, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Ehab Atallah, MD Bruce M. White Associate Professor of Medicine, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI SENIOR EDITOR Robert Litchkofski EXECUTIVE VICE PRESIDENT Barbara T. White EXECUTIVE DIRECtor OF OPERAtions Table of Contents Jean M. Gaul Introduction ................................. 1 Epidemiology, Etiology, and Pathogenesis ........ 1 Clinical Features ........................... 1 Merck is pleased to provide this Classification and Risk Stratification ............ 2 material as a professional service to the medical community. Molecular Basis of MDS ..................... 4 Intermediate-1-Risk MDS ................... 5 5Q-Deletion Syndrome ..................... 8 High-Risk MDS with Del(5q) .................. 9 High-Risk MDS ........................... 10 NOTE FROM THE PUBLISHER: Summary ............................... 11 This publication has been developed with­ out involvement of or review by the Amer­ Board Review Questions .................... 11 ican Board of Internal Medicine. References ................................. 11 Copyright 2014, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. 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, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications.
    [Show full text]
  • Impaired Hematopoiesis and Leukemia Development in Mice with a Conditional Knock-In Allele of a Mutant Splicing Factor Gene U2af1
    Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1 Dennis Liang Feia,b,c,1,2, Tao Zhend,1, Benjamin Durhame, John Ferraronea,b, Tuo Zhangf,g, Lisa Garretth, Akihide Yoshimie, Omar Abdel-Wahabe,i, Robert K. Bradleyj,k, Paul Liud,2, and Harold Varmusa,b,c,l,2 aDepartment of Medicine, Weill Cornell Medicine, New York, NY 10065; bMeyer Cancer Center, Weill Cornell Medicine, New York, NY 10065; cCancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; dOncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; eHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; fGenomics Resources Core Facility, Weill Cornell Medicine, New York, NY 10065; gDepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; hEmbryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; iLeukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065; jComputational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; kBasic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and lNew York Genome Center, New York, NY 10013 Contributed by Harold Varmus, September 15, 2018 (sent for review July 26, 2018; reviewed by Benjamin L. Ebert and Stephanie Halene) Mutations affecting the spliceosomal protein U2AF1 are commonly addition, U2AF1(S34F) is present at high allelic frequencies (nearly found in myelodysplastic syndromes (MDS) and secondary acute 50%) in MDS (6), seems to predispose MDS patients to secondary myeloid leukemia (sAML).
    [Show full text]
  • Immunophenotypic Analysis of Erythroid Dysplasia in Myelodysplastic Syndromes
    Myelodysplastic Syndrome SUPPLEMENTARY APPENDIX Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDSFlow working group Theresia M. Westers, 1 Eline M.P. Cremers, 1 Uta Oelschlaegel, 2 Ulrika Johansson, 3 Peter Bettelheim, 4 Sergio Matarraz, 5 Alberto Orfao, 5 Bijan Moshaver, 6 Lisa Eidenschink Brodersen, 7 Michael R. Loken, 7 Denise A. Wells, 7 Dolores Subirá, 8 Matthew Cullen, 9 Jeroen G. te Marvelde, 10 Vincent H.J. van der Velden, 10 Frank W.M.B. Preijers, 11 Sung-Chao Chu, 12 Jean Feuillard, 13 Estelle Guérin, 13 Katherina Psarra, 14 Anna Porwit, 15,16 Leonie Saft, 16 Robin Ireland, 17 Timothy Milne, 17 Marie C. Béné, 18 Birgit I. Witte, 19 Matteo G. Della Porta, 20 Wolfgang Kern 21 and Arjan A. van de Loosdrecht, 1 on behalf of the IMDSFlow Working Group 1Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, The Netherlands; 2Department of Internal Medi - cine, Universitätsklinikum “Carl-Gustav-Carus”, Dresden, Germany; 3Department of Haematology, University Hospitals NHS Foundation Trust, Bristol, UK; 4First Medical Department, Elisabethinen Hospital, Linz, Austria; 5Servicio Central de Citometría (NUCLEUS) and De - partment of Medicine, Centro de Investigación del Cáncer, Instituto de Biologia Celular y Molecular del Cáncer, (CSIC/USAL and IBSAL), Universidad de Salamanca, Spain; 6Isala Clinics, Zwolle, The Netherlands; 7HematoLogics, Inc., Seattle, WA, USA; 8Department of Hematology, Hospital Universitario de Guadalajara, Spain; 9HMDS, St. James’s University
    [Show full text]
  • Proposed Minimal Diagnostic Criteria for Myelodysplastic Syndromes (MDS) and Potential Pre-MDS Conditions
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 43), pp: 73483-73500 Priority Review Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions Peter Valent1,2, Attilio Orazi3, David P. Steensma4, Benjamin L. Ebert5, Detlef Haase6, Luca Malcovati7, Arjan A. van de Loosdrecht8, Torsten Haferlach9, Theresia M. Westers8, Denise A. Wells10, Aristoteles Giagounidis11, Michael Loken10, Alberto Orfao12, Michael Lübbert13, Arnold Ganser14, Wolf-Karsten Hofmann15, Kiyoyuki Ogata16, Julie Schanz6, Marie C. Béné17, Gregor Hoermann18, Wolfgang R. Sperr1,2, Karl Sotlar19, Peter Bettelheim20, Reinhard Stauder21, Michael Pfeilstöcker22, Hans- Peter Horny23, Ulrich Germing24, Peter Greenberg25 and John M. Bennett26 1 Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria 2 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria 3 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA 4 Division of Hematological Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 5 Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 6 Clinic of Hematology and Medical Oncology, Universitymedicine Göttingen, Göttingen, Germany 7 Department of Molecular Medicine, University of Pavia, Pavia, Italy 8 Department of Hematology Cancer Center Amsterdam,
    [Show full text]