Atlas Journal

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 7, Number 4, Oct-Dec 2003 Previous Issue / Next Issue Genes DAB2IP (DAB2 interacting protein) (9q34). Anne RM von Bergh. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 448-451. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/AF9q34ID316.html ALK (anaplastic lymphoma kinase) (2p23) - updated. Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 452-460. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ALK.html ALO17 (ALK lymphoma oligomerization partner on chromosome 17) (17q25). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 461-463. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ALO17ID480.html CARS (cysteinyj-tRNA synthetase) - (11p15.5). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 464-467. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CARSID484.html CLTC (clathrin heavy polypeptide) - updated. Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 468-473. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CLTCID360.html CLTCL1 (clathrin heavy polypeptide-like 1) (22q11) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 474-478. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 I URL : http://AtlasGeneticsOncology.org/Genes/CLTCL1ID361.html LAF4 (lymphoid nuclear protein related to AF4) (2q11.2-2q12). Anne RM von Bergh. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 479-482. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/LAF4ID315.html MYH9 (myosin, heavy polypeptide 9, non-muscle) (22q12). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 483-487. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MYH9ID481.html RANBP2 (RAN binding protein) (2q13). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 488-491. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RANBP2ID483.html REG-IV (regenerating gene type IV) (1p12). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 492-494. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/REGIVID485.html IGH (Immunoglobulin Heavy) (14q32.33) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 495-506. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/IgHID40.html IGK (Immunoglobulin Kappa) (2p12) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 507-513. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/IgKID17.html IGL (Immunoglobulin Lambda) (22q11.2) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 514-520. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/IgLID54.html TRA (T cell Receptor Alpha) (14q11.2) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 521-527. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TCRAID39.html TRB (T cell Receptor Beta) (7q35) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 528-533. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TCRBID24.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 II TRD (T cell Receptor Delta) (14q11.2) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 534-539. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TCRDID279.html TRG (T cell Receptor Gamma) (7p15-p14) - updated. Marie-Paule Lefranc. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 540-543. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TCRGID268.html Leukaemias 11q23 rearrangements in leukaemia - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 544-554. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/11q23ID1030.html Anaplasic large cell lymphoma (ALCL) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 555-562. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/AnaplLargeCelLymphID2103.html t(1;7)(p34;q34). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 563-565. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0107p34q34ID1045.html t(2;17)(p23;q25). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 566-568. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0217p23q25ID1289.html t(2;17)(p23;q23). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 569-571. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0217p23q23ID1290.html t(2;22)(p23;q11.2). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 572-574. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0222p23q11D1291.html t(16;21)(q24;q22) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 576-578. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1621ID1123.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 III 15q13-15 Rearrangements. Nyla A Heerema. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 579-580. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/15q13rearID1257.html +18 or trisomy 18 in lymphoproliferative disorders. Daniel L Van Dyke. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 581-586. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/Tri18ID2030.html Solid Tumours Soft tissue tumors: Inflammatory myofibroblastic tumor - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 587-590. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/MyofibroID5073.html Ovary: Germ cell tumors. Lisa Lee-Jones. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 591-606. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/OvarianGermCellID5067.html t(2;2)(p23;q13). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 607-608. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/t0202p23q13ID5214.html t(2;11)(p23;p15) . Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 609-610. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/t0211p23p15ID5213.html Cancer Prone Diseases Deep Insights Comparative Cancer Cytogenetics. Nicole McNeil, Cristina Montagna, Michael J Difilippantonio, Thomas Ried. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 611-636. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/ComparCancerCytogID20011.html MLL: Deep Insight. Jay L Hess. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 637-653. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/MLLdeepID20005.html Case Reports

Atlas Genet Cytogenet Oncol Haematol 2003; 4 IV Educational Items

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Atlas Genet Cytogenet Oncol Haematol 2003; 4 V Atlas of Genetics and Cytogenetics in Oncology and Haematology

DAB2IP (DAB2 interacting protein)

Identity Note centromeric of ABL Other names AF9q34 DIP1/2,

KIAA1743 Hugo DAB2IP Location 9q34 Note centromeric of ABL DNA/RNA Description 14 exons stretched over an area of about 84 kb. Exon 1, a noncoding exon, has (at least) three variants. Transcription in a centromere to telomere direction 5192 bp mRNA; 2903 bp open reading frame. Protein

Description The AF9q34 protein contains a GAP related domain (GRD), an 'FLR'-motif, a Pleckstrin homology (PH) domain and a calcium/phospho-lipid-binding C2/CALB domain; 967 amino acids. Expression Expression in all human tissues with a relatively low level of expression in testis, placenta, spleen and peripheral blood leukocytes. Function RasGAPs negatively regulate the activity of Ras proteins that modulate diverse cellular processes by cycling between the inactive GDP-bound and active GTP- bound state. DAB2 interacting protein. Homology Homologous to human nGAP (or RAS protein activator like 2 (RASAL2)). Implicated in Entity t(9;11)(q34;q23) AML --> MLL-AF9q34 Note Another t(9;11)(q34;q23) AML has been reported with involvement of MLL-FBP17. Disease Only one case to date, a 62 yr old male patient with Acute Myeloid Leukemia (M5). Cytogenetics The case was 46, XY, t(9;11)(q34;q23) and in 40% of the metaphases additional chromosomes 8 and 13 were observed.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -448-

Schematic representation of MLL, AF9q34, and the putative MLL-AF9q34 fusion protein. Domains in MLL and AF9q34 are shaded: AT, AT-hook DNA binding motifs; SNL1 and SNL2, speckled nuclear localisation signals 1 and 2; CxxC, cysteine rich motif homologous to DNA methyltransferase (MT); PHD, plant homeodomain fingers; FYRN, FYRN domain; FYRC. FYRC domain; SET, SET domain; PH, Pleckstrin Homology Domain; GRD, GAP Related Domain. Arrows indicate the breakpoint (bp) sites in MLL and AF9q34. Hybrid/Mutated 5' MLL fused at exon 9 with the 3' end of AFq34. Gene Abnormal The MLL-AF9q34 protein includes the entire GAP related domain (GRD) Protein and the C2/CALB domain, but the PH domain is disrupted by the breakpoint in AF9q34. External links

Nomenclature Hugo DAB2IP GDB DAB2IP Entrez_Gene DAB2IP 153090 DAB2 interacting protein Cards Atlas AF9q34ID316 GeneCards DAB2IP Ensembl DAB2IP Genatlas DAB2IP GeneLynx DAB2IP eGenome DAB2IP euGene 153090 Genomic and cartography DAB2IP - 9q34 chr9:123501470-123587628 + 9q33.2 (hg18- GoldenPath Mar_2006) Ensembl DAB2IP - 9q33.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene DAB2IP

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -449- Gene and transcription

Genbank AB051530 [ ENTREZ ]

Genbank AF367051 [ ENTREZ ]

Genbank AK054851 [ ENTREZ ]

Genbank AK096391 [ ENTREZ ]

Genbank AK124610 [ ENTREZ ]

RefSeq NM_032552 [ SRS ] NM_032552 [ ENTREZ ]

RefSeq NM_138709 [ SRS ] NM_138709 [ ENTREZ ] AceView DAB2IP AceView - NCBI TRASER DAB2IP Traser - Stanford

Unigene Hs.522378 [ SRS ] Hs.522378 [ NCBI ] HS522378 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q5T4Q1 [ SRS] Q5T4Q1 [ EXPASY ] Q5T4Q1 [ INTERPRO ]

Prosite PS50003 PH_DOMAIN [ SRS ] PS50003 PH_DOMAIN [ Expasy ]

Interpro IPR000008 C2_Ca-dep [ SRS ] IPR000008 C2_Ca-dep [ EBI ]

Interpro IPR008973 C2_CaLB [ SRS ] IPR008973 C2_CaLB [ EBI ]

Interpro IPR001849 PH [ SRS ] IPR001849 PH [ EBI ]

Interpro IPR011993 PH_type [ SRS ] IPR011993 PH_type [ EBI ] CluSTr Q5T4Q1

Pfam PF00168 C2 [ SRS ] PF00168 C2 [ Sanger ] pfam00168 [ NCBI-CDD ]

Pfam PF00169 PH [ SRS ] PF00169 PH [ Sanger ] pfam00169 [ NCBI-CDD ]

Smart SM00239 C2 [EMBL]

Smart SM00233 PH [EMBL] Blocks Q5T4Q1 HPRD Q5T4Q1 Protein Interaction databases DIP Q5T4Q1 IntAct Q5T4Q1 Polymorphism : SNP, mutations, diseases OMIM 609205 [ map ] GENECLINICS 609205

SNP DAB2IP [dbSNP-NCBI]

SNP NM_032552 [SNP-NCI]

SNP NM_138709 [SNP-NCI]

SNP DAB2IP [GeneSNPs - Utah] DAB2IP] [HGBASE - SRS]

HAPMAP DAB2IP [HAPMAP]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -450- General knowledge

Family Browser DAB2IP [UCSC Family Browser] SOURCE NM_032552 SOURCE NM_138709 SMD Hs.522378 SAGE Hs.522378 Amigo GTPase activator activity Amigo intracellular Amigo regulation of small GTPase mediated signal transduction PubGene DAB2IP Other databases

Probes Probe clones RP6-10F14 and RP6-105L9 Probe DAB2IP Related clones (RZPD - Berlin) PubMed PubMed 15 Pubmed reference(s) in LocusLink Bibliography Cloning of unknown MLL fusion transcripts identifies two novel MLL fusion partners. von Bergh A, Beverloo B, Slater R, Groot A, Rombout P, Kluin P, Schuuring E. Blood 2000; 96 Suppl 1: Abst 2984.

Differential regulation of the human gene DAB2IP in normal and malignant prostatic epithelia: cloning and characterization. Chen H, Pong RC, Wang Z, Hsieh JT. Genomics 2002; 79(4): 573-581. Medline 21945266 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08-2003 Anne RM von Bergh Citation This paper should be referenced as such : von Bergh ARM . DAB2IP (DAB2 interacting protein). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Genes/AF9q34ID316.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -451- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALK (anaplastic lymphoma kinase)

Identity Hugo ALK Location 2p23

ALK (2p23) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Transcription 6226 bp cDNA; coding sequence: 4.9 kb Protein

Description 1620 amino acids; 177 kDa; after glycosylation, produces a 200 kDa mature glycoprotein; composed of an extracellular domain, a transmembrane domain, a tyrosine kinase domain, and an intracytoplasmic domain in C-term; dimerization Expression is tissue specific; mainly in: brain, gut and testis; not in the lymphocytes Localisation cell membrane

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -452- Function membrane associated tyrosine kinase receptor; probable role in the nervous system development and maintenance Homology homologies with the insulin receptor super family: LTK (leucocyte tyrosine kinase), TRKA, ROS (homolog of the drosophila Sevenless), IGF1-R, IRb Implicated in Entity Anaplasic large cell lymphoma (ALCL) with t(2;5)(p23;q35) --> NPM1-ALK Disease ALCL are high grade non Hodgkin lymphomas; ALK+ ALCL are ALCL where ALK is involved in a fusion gene; ALK+ ALCL represent 50 to 60 % of ALCL cases (they are CD30+, ALK+;); 70 to 80% of ALK+ ALCL cases bear a t(2;5); the remaining ALK+ ALCL cases bear variant translocations described below and are called "cytoplasmic ALK+" cases, of which is the t(1;2) TPM3/ALK, found in 20% of ALK+ ALCL. Prognosis althouth presenting as a high grade tumour, a 80% five yr survival is associated with this anomaly Cytogenetics additional anomalies and complex karyotypes are most often found Hybrid/Mutated 5' NPM1-3' ALK on the der(5) Gene Abnormal 680 amino acids, 80 kDa; N-term 116 amino acids from NPM1 fused Protein to the 562 C-term aminoacids of ALK (i.e. composed of the oligomerization domain and the metal binding site of NPM1, and the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart. Characteristic localisation both in the cytoplasm and in the nucleus, due to heterooligomerization of NPM- ALK and normal NPM whereas the normal NPM protein is confined to the nucleus; constitutive activation of the catalytic domain of ALK. Oncogenesis via the kinase function activated by oligomerization of NPM1-ALK mediated by the NPM1 part

Entity Cytoplasmic ALK+ anaplasic large cell lymphoma Prognosis present a favourable prognosis comparable to the one found in t(2;5) ALK+ ALCL. Cytogenetics Either

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -453- ALK, which should lead to constitutive autophosphorylation and activation of the ALK tyrosine kinase, as for NPM1-ALK (see t(2;5)(p23;q35) ).

Entity Inflammatory myofibroblastic tumours with 2p23 rearrangements Disease rare soft tissue tumour found in children and young adults about one third to half of inflammatory myofibroblastic tumour cases present with a 2p23 rearrangement involving ALK. Prognosis good prognosis Cytogenetics t(1;2)(q25;p23), t(2;2)(p23;q13), t(2;11)(p23;p15), t(2;17)(p23;q23) , or t(2;19)(p23;p13.1) so far Hybrid/Mutated 5' TPM3 in the t(1;2), RANBP2 in the t(2;2), CARS in the t(2;11), 5' Gene CLTC in the t(2;17), or 5' TPM4 in the t(2;19)- 3' ALK Abnormal N-term amino acids from the partner gene fused to the 562 C-term Protein amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected. Oncogenesis fused-ALK is contitutively activated

Breakpoints

Note Most of the breakpoints occur in the same intron of ALK, whichever partner is involved in the fusion protein To be noted ALK and some of the above ALK partners, or closely related genes, are found implicated both in anaplasic large cell lymphoma and in Inflammatory myofibroblastic tumours; this is a new concept, that 2 different types of tumour may result from the same chromosomal/genes

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -454- rearrangement. External links Nomenclature Hugo ALK GDB ALK Entrez_Gene ALK 238 anaplastic lymphoma kinase (Ki-1) Cards Atlas ALK GeneCards ALK Ensembl ALK CancerGene ALK Genatlas ALK GeneLynx ALK eGenome ALK euGene 238 Genomic and cartography ALK - 2p23 chr2:29327293-30056083 - 2p23.2 (hg17- GoldenPath May_2004) Ensembl ALK - 2p23.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ALK Gene and transcription

Genbank D45915 [ SRS ] D45915 [ ENTREZ ]

Genbank U04946 [ SRS ] U04946 [ ENTREZ ]

Genbank U62540 [ SRS ] U62540 [ ENTREZ ]

Genbank U66559 [ SRS ] U66559 [ ENTREZ ]

RefSeq NM_004304 [ SRS ] NM_004304 [ ENTREZ ]

RefSeq NT_086610 [ SRS ] NT_086610 [ ENTREZ ] AceView ALK AceView - NCBI TRASER ALK Traser - Stanford

Unigene Hs.196534 [ SRS ] Hs.196534 [ NCBI ] HS196534 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9UM73 [ SRS] Q9UM73 [ EXPASY ] Q9UM73 [ INTERPRO ]

Prosite PS01209 LDLRA_1 [ SRS ] PS01209 LDLRA_1 [ Expasy ]

Prosite PS50068 LDLRA_2 [ SRS ] PS50068 LDLRA_2 [ Expasy ]

Prosite PS00740 MAM_1 [ SRS ] PS00740 MAM_1 [ Expasy ]

Prosite PS50060 MAM_2 [ SRS ] PS50060 MAM_2 [ Expasy ]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -455- PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 Prosite PROTEIN_KINASE_TYR [ Expasy ]

PS00239 RECEPTOR_TYR_KIN_II [ SRS ] PS00239 Prosite RECEPTOR_TYR_KIN_II [ Expasy ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR002172 LDL_receptor_A [ SRS ] IPR002172 LDL_receptor_A [ EBI ]

Interpro IPR000998 MAM [ SRS ] IPR000998 MAM [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]

Interpro IPR002011 RecepttyrkinsII [ SRS ] IPR002011 RecepttyrkinsII [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] CluSTr Q9UM73

Pfam PF00629 MAM [ SRS ] PF00629 MAM [ Sanger ] pfam00629 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00192 LDLa [EMBL]

Smart SM00219 TyrKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom Q9UM73 ALK_HUMAN [ Domain structure ] Q9UM73 ALK_HUMAN [ sequences sharing at least 1 domain ] Blocks Q9UM73 Polymorphism : SNP, mutations, diseases OMIM 105590 [ map ] GENECLINICS 105590

SNP ALK [dbSNP-NCBI]

SNP NM_004304 [SNP-NCI]

SNP ALK [GeneSNPs - Utah] ALK [SNP - CSHL] ALK] [HGBASE - SRS] General knowledge Family ALK [UCSC Family Browser] Browser SOURCE NM_004304 SMD Hs.196534 SAGE Hs.196534

2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG Enzyme ] 2.7.1.112 [ WIT ] Amigo function|ATP binding

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -456- Amigo process|N-linked glycosylation Amigo component|integral to membrane Amigo process|neurogenesis Amigo process|protein amino acid phosphorylation Amigo function|receptor activity Amigo function|transferase activity Amigo function|transmembrane receptor protein tyrosine kinase activity process|transmembrane receptor protein tyrosine kinase signaling Amigo pathway PubGene ALK Other databases Probes Probe Cancer Cytogenetics (Bari) Probe ALK Related clones (RZPD - Berlin) PubMed PubMed 25 Pubmed reference(s) in LocusLink Bibliography Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non- Hodgkin's lymphoma. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT Science 1994 Mar 4;263(5151):1281-4 Published erratum appears in Science 1995 Jan 20;267(5196):316-7 Medline 94167588

Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T Oncogene 1997 Jan 30;14(4):439-49 Medline 97178863

ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase. Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP Oncogene 1997 May 8;14(18):2175-88 Published erratum appears in Oncogene 1997 Dec 4;15(23):2883 Medline 97316779

Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma- associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Bischof D, Pulford K, Mason DY, Morris SW

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -457- Mol Cell Biol 1997 Apr;17(4):2312-25 Medline 97220023

Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Cancer Res 1999, 59: 2776-2780.

TRK-Fused Gene (TFG) Is a New Partner of ALK in Anaplastic Large Cell Lymphoma Producing Two Structurally Different TFG-ALK Translocations. Hernandez L, Pinyol M, Hernandez S, Bea S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E. Blood 1999; 94: 3265-3268.

A New Fusion Gene TPM3-ALK in Anaplastic Large Cell Lymphoma Created by a (1;2)(q25;p23) Translocation. Lamant L, Dastugue N, Pulford K, Delsol G, Mariam+ B. Blood 1999; 93: 3088-3095.

Complex variant translocation t(1;2) with TPM3-ALK fusion due to cryptic ALK gene rearrangement in anaplastic large cell lymphoma. Siebert R, Gest S, Harder L, Steinemann D, Grote W, Schlegelberger B, Tiemann M, Wlodarska I, Schemmel V. Blood 1999; 94: 3614-3617.

TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CDM, Fletcher JA. Am J Pathol 2000, 157: 377-384.

ATIC-ALK: A Novel Variant ALK Gene Fusion in Anaplastic Large Cell Lymphoma Resulting from the Recurrent Cryptic Chromosomal Inversion, inv(2)(p23q35). Colleoni GWB, Bridge JA, Garicochea B, Liu J, Filippa DA, Ladanyi M. Am J Pathology 2000; 156: 781-789.

Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. Ma Z, Cools J,Marynen P, Cui X, Siebert R, Gesk S, Schlegelberger B, De Wolf- Peeters C, Wlodarska I, Morris SW. Blood 2000; 95: 2144-2149.

A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma. Trinei M, Lanfrancone L, Campo E, Pulford K, Mason DY, Pelicci PG, Falini B. Cancer Res 2000; 60: 793-798.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -458-

CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B. Blood 2000; 96: 3681-3695.

Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Touriol C, Greenland C, Lamant L, Pulford K, Bernard F, Rousset T, Mason DY, Delsol G. Blood 2000; 95: 3204-3207.

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG. Leukemia 2000; 14: 1533-1559.

Fusion of the ALK Gene to the Clathrin Heavy Chain Gene, CLTC, in Inflammatory Myofibroblastic Tumor. Bridge JA, Kanamori M, Ma Z, Pickering D, D. Hill A, Lydiatt W, Lui MY, Colleoni GWB, Antonescu CR, Ladanyi M, Morris SW. Am J Pathol 2001; 159: 411-415.

Molecular characterization of a new ALK translocation involving moesin (MSN- ALK) in anaplasic large cell lymphoma. Tort F, Pinyol M, Pulford K, Roncador G, Hernandez L, Nayach I, Kluin-Nelemans HC, Kluin P, Touriol C, Delsol G, Mason D, Campo E. Lab Invest 2001; 81: 419-426.

Anaplastic large cell lymphomas, Primary systemic (T/Null cell type). Delsol G, Ralfkiaer E, Stein H, Wright D, Jaffe E. World Health Organization (WHO) Classification of Tumors. Pathology and Genetics of tumours of Haematopoietic and Lymphoid Tissues . 2001 pp 230-235.

Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Morris SW, Xue L, Ma Z, Kinney MC. Br J Haematol 2001; 113: 275-295. Medline 21275125

Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P. Genes Chromosomes Cancer 2002; 34: 354-362. Medline 12112524

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -459-

Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. Lamant L, Gascoyne RD, Duplantier MM, Armstrong F, Raghab A, Chhanabhai M, Rajcan-Separovic E, Raghab J, Delsol G, Espinos E. Genes Chromosomes Cancer 2003; 37: 427-432. Medline 12800156

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 09- Jean-Loup Huret 1997 Updated 08- Jean-Loup Huret 2001 Updated 08- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL . ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol. September 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ALK.html Huret JL . ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ALK.html Huret JL, Senon S . ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ALK.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -460- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALO17 (ALK lymphoma oligomerization partner on chromosome 17)

Identity Location 17q25 DNA/RNA Transcription alternate spicing; 5185 and 5332 bp cDNA Protein

Description 1550 and 1599 amino acids if the sequence is complete; putative zinc finger in the N term, and AraC motif in the C term Implicated in Entity Anaplasic large cell lymphoma (ALCL) with t(2;17)(p23;q25) --> ALK- ALO17 Disease ALCL are high grade non Hodgkin lymphomas; ALK+ ALCL are ALCL where ALK is involved in a fusion gene; ALK+ ALCL represent 50 to 60 % of ALCL cases (they are CD30+, ALK+;); belong to the "cytoplasmic ALK+" subset. Prognosis Althouth presenting as a high grade tumour, a 80% five yr survival is associated with this anomaly Hybrid/Mutated 5' ALO17 - 3' ALK Gene Abnormal NH2 ALO17 - COOH ALK Protein

External links

Nomenclature GDB KIAA1618 Entrez_Gene KIAA1618 57714 KIAA1618 Cards Atlas ALO17ID480 GeneCards KIAA1618

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -461- Ensembl KIAA1618 Genatlas KIAA1618 GeneLynx KIAA1618 eGenome KIAA1618 euGene 57714 Genomic and cartography KIAA1618 - 17q25 chr17:75849262-75909855 + 17q25.3 (hg18- GoldenPath Mar_2006) Ensembl KIAA1618 - 17q25.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene KIAA1618 Gene and transcription

Genbank AB046838 [ ENTREZ ]

Genbank AF397204 [ ENTREZ ]

Genbank AF397205 [ ENTREZ ]

Genbank AK023113 [ ENTREZ ]

Genbank AL832920 [ ENTREZ ]

RefSeq NM_020954 [ SRS ] NM_020954 [ ENTREZ ] AceView KIAA1618 AceView - NCBI TRASER KIAA1618 Traser - Stanford

Unigene Hs.514554 [ SRS ] Hs.514554 [ NCBI ] HS514554 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q69YK7 [ SRS] Q69YK7 [ EXPASY ] Q69YK7 [ INTERPRO ] CluSTr Q69YK7 Blocks Q69YK7 HPRD Q69YK7 Protein Interaction databases DIP Q69YK7 IntAct Q69YK7 Polymorphism : SNP, mutations, diseases

SNP KIAA1618 [dbSNP-NCBI]

SNP NM_020954 [SNP-NCI]

SNP KIAA1618 [GeneSNPs - Utah] KIAA1618] [HGBASE - SRS]

HAPMAP KIAA1618 [HAPMAP] General knowledge

Family KIAA1618 [UCSC Family Browser]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -462- Browser SOURCE NM_020954 SMD Hs.514554 SAGE Hs.514554 PubGene KIAA1618 Other databases

Probes

PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P. Genes Chromosomes Cancer 2002; 34: 354-362. Medline 12112524

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08-2003 Jean-Loup Huret, Sylvie Senon Citation This paper should be referenced as such : Huret JL, Senon S . ALO17 (ALK lymphoma oligomerization partner on chromosome 17). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Genes/ALO17ID480.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -463- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CARS (cysteinyj-tRNA synthetase)

Identity Other names cysteine-tRNA ligase cysteinease-translase Hugo CARS Location 11p15.5 700 kb telomeric to NUP98 DNA/RNA Description The gene spans 57 kb; 22 exons; 2,5 kb cDNA Transcription alternate splicing Protein

Description 748 amino acids, 85 kDa. Forms homodimers Localisation cytoplasmic Implicated in Entity Inflammatory myofibroblastic tumors with a complex t(2;11)(p23;p15) Disease rare soft tissue tumour found in children and young adults Prognosis good prognosis Hybrid/Mutated 5' CARS - 3' ALK Gene Abnormal N-term CARS (606 amino acids) fused to the usual 562 C-term amino acids Protein of ALK

External links

Nomenclature Hugo CARS GDB CARS Entrez_Gene CARS 833 cysteinyl-tRNA synthetase Cards

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -464- Atlas CARSID484 GeneCards CARS Ensembl CARS Genatlas CARS GeneLynx CARS eGenome CARS euGene 833 Genomic and cartography GoldenPath CARS - 11p15.5 chr11:2978736-3035247 - 11p15.4 (hg18-Mar_2006) Ensembl CARS - 11p15.4 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CARS Gene and transcription

Genbank AB208814 [ ENTREZ ]

Genbank AF288206 [ ENTREZ ]

Genbank AF288207 [ ENTREZ ]

Genbank AK096313 [ ENTREZ ]

Genbank AK125503 [ ENTREZ ]

RefSeq NM_001014437 [ SRS ] NM_001014437 [ ENTREZ ]

RefSeq NM_001014438 [ SRS ] NM_001014438 [ ENTREZ ]

RefSeq NM_001751 [ SRS ] NM_001751 [ ENTREZ ]

RefSeq NM_139273 [ SRS ] NM_139273 [ ENTREZ ] AceView CARS AceView - NCBI TRASER CARS Traser - Stanford

Unigene Hs.274873 [ SRS ] Hs.274873 [ NCBI ] HS274873 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P49589 [ SRS] P49589 [ EXPASY ] P49589 [ INTERPRO ] Prosite PS00178 AA_TRNA_LIGASE_I [ SRS ] PS00178 AA_TRNA_LIGASE_I [ Expasy ] Interpro IPR002308 Cys_tRNA-synt_1a [ SRS ] IPR002308 Cys_tRNA-synt_1a [ EBI ]

Interpro IPR001412 tRNA-synt_I [ SRS ] IPR001412 tRNA-synt_I [ EBI ] CluSTr P49589 Pfam PF01406 tRNA-synt_1e [ SRS ] PF01406 tRNA-synt_1e [ Sanger ] pfam01406 [ NCBI-CDD ] Blocks P49589 HPRD P49589

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -465- Protein Interaction databases DIP P49589 IntAct P49589 Polymorphism : SNP, mutations, diseases OMIM 123859 [ map ] GENECLINICS 123859

SNP CARS [dbSNP-NCBI]

SNP NM_001014437 [SNP-NCI]

SNP NM_001014438 [SNP-NCI]

SNP NM_001751 [SNP-NCI]

SNP NM_139273 [SNP-NCI] SNP CARS [GeneSNPs - Utah] CARS] [HGBASE - SRS]

HAPMAP CARS [HAPMAP] General knowledge

Family Browser CARS [UCSC Family Browser] SOURCE NM_001014437 SOURCE NM_001014438 SOURCE NM_001751 SOURCE NM_139273 SMD Hs.274873 SAGE Hs.274873

Enzyme 6.1.1.16 [ Enzyme-SRS ] 6.1.1.16 [ Brenda-SRS ] 6.1.1.16 [ KEGG ] 6.1.1.16 [ WIT ] Amigo tRNA binding Amigo nucleotide binding Amigo cysteine-tRNA ligase activity Amigo receptor activity Amigo ATP binding Amigo soluble fraction Amigo cytoplasm Amigo protein biosynthesis Amigo cysteinyl-tRNA aminoacylation Amigo zinc ion binding Amigo ligase activity Amigo metal ion binding KEGG Cysteine Metabolism KEGG Aminoacyl-tRNA Biosynthesis PubGene CARS

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -466- Other databases

Probes Probe CARS Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P. Genes Chromosomes Cancer 2002; 34: 354-362. Medline 12112524

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08-2003 Jean-Loup Huret, Sylvie Senon Citation This paper should be referenced as such : Huret JL, Senon S . CARS (cysteinyj-tRNA synthetase). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Genes/CARSID484.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -467- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CLTC (clathrin heavy polypeptide) (updated: old version not available)

Identity Note must not be confused with CLTCL1 (clathrin heavy polypeptide-like 1). Other names clathrin heavy chain KIAAOO34

CLH-17 Hugo CLTC Location 17q23 Note must not be confused with CLTCL1 (clathrin heavy polypeptide-like 1). DNA/RNA Transcription 32 exons, 6111 bp mRNA Protein

Description Clathrin is the major protein constituent of the coat that surrounds organelles (cytoplasmic vesicles) to mediate selective protein transport. Clathrin coats are involved in receptor-mediated endocytosis and intracellular trafficking and recycling of receptors, which accounts for its characteristic punctate cytoplasmic and perinuclear cellular distribution. Structurally, clathrin is a triskelion (three-legged) shaped protein complex that is composed of a trimer of heavy chains (CLTC) each bound to a single light chain. CLTC is a 1675 amino acid residue protein encoded by a gene consisting of 32 exons. Its known domains include a N-terminal globular domain (residues 1-494) that interacts with adaptor proteins (AP-1, AP-2, b-arrestin), a light chain-binding region (residues 1074-1552), and a trimerization domain (residues 1550-1600) near the C-terminus. Localisation Cytoplasmic vesicles Function mediate endocytosis of transmembrane receptors. Implicated in Entity Anaplasic large cell lymphoma (ALCL) with t(2;17)(p23;q23) --> ALK - CLTC Disease ALCL are high grade non Hodgkin lymphomas; ALK+ ALCL are ALCL where ALK is involved in a fusion gene; ALK+ ALCL represent 50 to 60 % of ALCL cases (they are CD30+, ALK+;); belong to the "cytoplasmic

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -468- ALK+" subset. Prognosis Although presenting as a high grade tumour, a 80% five yr survival is associated with this anomaly Hybrid/Mutated 5' CLTC - 3' ALK Gene Abnormal NH2 CLTC - COOH ALK Protein

Entity Inflammatory myofibroblastic tumors with t(2;17)(p23;q23) Note In these tumors, the fusion point in CLTC is identical, being at amino acid 1634 (corresponding to the 3' end of exon 31 of CLTC), such that almost all of CLTC is included in the fusion protein, including its trimerization domain . As a fusion partner, CLTC has been postulated to provide CLTC-ALK with deregulated expression driven by its constitutively activated promoter and constitutive oligomerization of the chimeric protein via the CLTC multimerization domains normally used for clathrin coat assembly. Since ALK is a tyrosine kinase that is activated by cross-phosphorylation following ligand binding, CLTC-ALK-induced oligomerization may result in a constitutively activated ALK tyrosine kinase domain. In this sense, CLTC is likely to function in CLTC-ALK as other prototypical "dimerizing translocation partners" in fusions involving tyrosine kinase genes. Disease rare soft tissue tumour found in children and young adults Prognosis good prognosis Hybrid/Mutated 5' CLTC - 3' ALK Gene

Entity Xp11 renal translocation carcinoma with t(X;17)(p11;q23) Note In the CLTC-TFE3 fusion, the fusion point on CLTC is at amino acid 932 (corresponding to the end of exon 17), thereby excluding the CLTC trimerization domain from the predicted fusion protein. As in other TFE3 gene fusions, the nuclear localization and DNA binding domains of TFE3 are retained in CLTC-TFE3. Based on these features and existing data on other TFE3 fusion proteins, CLTC-TFE3 may act as an aberrant transcription factor, with the CLTC promoter driving constitutive expression. Disease rare renal carcinoma (single case report) Prognosis Unknown prognosis Hybrid/Mutated 5' CLTC 3'TFE3 Gene

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -469-

External links

Nomenclature Hugo CLTC GDB CLTC Entrez_Gene CLTC 1213 clathrin, heavy polypeptide (Hc) Cards Atlas CLTCID360 GeneCards CLTC Ensembl CLTC Genatlas CLTC GeneLynx CLTC eGenome CLTC euGene 1213 Genomic and cartography GoldenPath CLTC - 17q23 chr17:55052038-55127254 + 17q23.1 (hg18-Mar_2006) Ensembl CLTC - 17q23.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CLTC Gene and transcription

Genbank AB073891 [ ENTREZ ]

Genbank AK127134 [ ENTREZ ]

Genbank BC015854 [ ENTREZ ]

Genbank BC036430 [ ENTREZ ]

Genbank BC051800 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -470- RefSeq NM_004859 [ SRS ] NM_004859 [ ENTREZ ] AceView CLTC AceView - NCBI TRASER CLTC Traser - Stanford

Unigene Hs.491351 [ SRS ] Hs.491351 [ NCBI ] HS491351 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q00610 [ SRS] Q00610 [ EXPASY ] Q00610 [ INTERPRO ]

Interpro IPR012331 Clathrin_H_link [ SRS ] IPR012331 Clathrin_H_link [ EBI ]

Interpro IPR001473 Clathrin_propl_N [ SRS ] IPR001473 Clathrin_propl_N [ EBI ]

Interpro IPR000547 Clathrin_repeat [ SRS ] IPR000547 Clathrin_repeat [ EBI ]

Interpro IPR011990 TPR-like_helical [ SRS ] IPR011990 TPR-like_helical [ EBI ] CluSTr Q00610

Pfam PF00637 Clathrin [ SRS ] PF00637 Clathrin [ Sanger ] pfam00637 [ NCBI-CDD ]

PF01394 Clathrin_propel [ SRS ] PF01394 Clathrin_propel [ Sanger Pfam ] pfam01394 [ NCBI-CDD ]

Smart SM00299 CLH [EMBL] Blocks Q00610 HPRD Q00610 Protein Interaction databases DIP Q00610 IntAct Q00610 Polymorphism : SNP, mutations, diseases OMIM 118955 [ map ] GENECLINICS 118955

SNP CLTC [dbSNP-NCBI]

SNP NM_004859 [SNP-NCI]

SNP CLTC [GeneSNPs - Utah] CLTC] [HGBASE - SRS]

HAPMAP CLTC [HAPMAP] General knowledge

Family Browser CLTC [UCSC Family Browser] SOURCE NM_004859 SMD Hs.491351 SAGE Hs.491351 Amigo structural molecule activity Amigo protein binding Amigo intracellular protein transport Amigo clathrin vesicle coat

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -471- Amigo clathrin coat of coated pit PubGene CLTC Other databases

Probes Probe CLTC Related clones (RZPD - Berlin) PubMed PubMed 61 Pubmed reference(s) in LocusLink Bibliography Structural domains of clathrin heavy chains. Kirchhausen T, Harrison SC J Cell Biol 1984; 99: 1725-1734. Medline 85030579

Clathrin heavy chain: molecular cloning and complete primary structure. Kirchhausen T, Harrison SC, Chow EP, Mattaliano RJ, Ramachandran KL, Smart J, Brosius J. Proc Natl Acad Sci U S A 1987; 84: 8805-8809. Medline 88097376

Human clathrin heavy chain (CLTC): partial molecular cloning, expression, and mapping of the gene to human chromosome 17q11-qter. Dodge GR, Kovalszky I, McBride OW, Yi HF, Chu ML, Saitta B, Stokes DG, Iozzo RV. Genomics 1991; 11: 174-178. Medline 92112210

Clathrin-coated vesicle formation and protein sorting: an integrated process. Schmid SL. Annu Rev Biochem 1997, 66: 511-548. Medline 9242916

Calthrin self-assembly is mediated by a tandemly repeated superhelix. Ybe JA, Brodsky FM, Hofman K, Lin K, Liu S-h, Chen L, Earnest TN, Fletterick RJ, Hwang PK. Nature 1999; 399: 371-375. Medline 10360576

Clathrin. Kirchhausen T. Annu Rev Biochem 2000; 69: 699-727. Medline 10966473

Fusion of the ALK Gene to the Clathrin Heavy Chain Gene, CLTC, in Inflammatory

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -472- Myofibroblastic Tumor. Bridge JA, Kanamori M, Ma Z, Pickering D, D. Hill A, Lydiatt W, Lui MY, Colleoni GWB, Antonescu CR, Ladanyi M, Morris SW. Am J Pathol 2001; 159: 411-415. Medline 11485898

A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X ;17)(p11.2 ;q23). Argani P, Lui MY, Couturier J, Bouvier R, Fournet J-C, Ladanyi M. Oncogene 2003; 22: 5374-5378. Medline 12917640

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08-2001 Jean-Loup Huret Updated 08-2003 Jean-Loup Huret, Sylvie Senon Updated 04-2005 Pedram Argani, Marc Ladanyi Citation This paper should be referenced as such : Huret JL . CLTC (clathrin heavy polypeptide). Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://AtlasGeneticsOncology.org/Genes/CLTCID360.html Huret JL, Senon S . CLTC (clathrin heavy polypeptide). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Genes/CLTCID360.html Argani P, Ladanyi M . CLTC (clathrin heavy polypeptide). Atlas Genet Cytogenet Oncol Haematol. April 2005 . URL : http://AtlasGeneticsOncology.org/Genes/CLTCID360.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -473- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CLTCL1 (clathrin heavy polypeptide-like 1) (updated: old version not available)

Identity Note may have been confused with CLTC (clathrin heavy chain gene), a partner gene of ALK. Other CLTCL names CLTD CLH-22 Hugo CLTCL1 Location 22q11 DNA/RNA Transcription 5564 bp mRNA Protein

Description 1640 amino acids, 187 kDa; is composed, from N-term to C-term, of: a globular domain (amino acids 1-479), , a linker (480-523), and the heavy chain arm (524-1640); properties: binding site for ATPase in N term, binding of the light chain in the C-term, and trimerization domain in the C-term. Subunit of clathrin, a structural protein composed of 3 heavy chains (CLTC, CLTCL1), and 2 light chains (CLTA, CLTB), which assembly is mediated by CALM. Form cages. Component of the vesicles matrix originated from the plasma membrane or the golgi Localisation vesicles Function mediate endocytosis of transmembrane receptors. Implicated in Entity ? t(2;22)(p23;q11.2)- ALK Note CLTCL1/ALK may in fact be cases of CLTC/ALK Disease ? found in a case of ALK+ anaplasic large cell lymphoma Abnormal ? 2197 amino acids, 248-250 kDa; 1634 (nearly all the CLTCL1 Protein protein) N-term amino acids from CLTCL1, fused to the 562 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); cytoplasmic localization restricted to granules Oncogenesis constitutive autophosphorylation

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -474-

External links Nomenclature Hugo CLTCL1 GDB CLTCL1 Entrez_Gene CLTCL1 8218 clathrin, heavy polypeptide-like 1 Cards Atlas CLTCL1ID361 GeneCards CLTCL1 Ensembl CLTCL1 Genatlas CLTCL1 GeneLynx CLTCL1 eGenome CLTCL1 euGene 8218 Genomic and cartography CLTCL1 - 22q11 chr22:17541543-17653762 - 22q11.21 (hg17- GoldenPath May_2004) Ensembl CLTCL1 - 22q11.21 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CLTCL1 Gene and transcription

Genbank U41763 [ SRS ] U41763 [ ENTREZ ]

Genbank U60802 [ SRS ] U60802 [ ENTREZ ]

Genbank U60803 [ SRS ] U60803 [ ENTREZ ]

Genbank X95486 [ SRS ] X95486 [ ENTREZ ]

Genbank X95487 [ SRS ] X95487 [ ENTREZ ]

RefSeq NM_001835 [ SRS ] NM_001835 [ ENTREZ ]

RefSeq NM_007098 [ SRS ] NM_007098 [ ENTREZ ]

RefSeq NT_086918 [ SRS ] NT_086918 [ ENTREZ ] AceView CLTCL1 AceView - NCBI TRASER CLTCL1 Traser - Stanford

Unigene Hs.368266 [ SRS ] Hs.368266 [ NCBI ] HS368266 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P53675 [ SRS] P53675 [ EXPASY ] P53675 [ INTERPRO ]

Interpro IPR008938 ARM [ SRS ] IPR008938 ARM [ EBI ] Interpro IPR001473 Clathrin_propl_N [ SRS ] IPR001473 Clathrin_propl_N [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -475- Interpro IPR000547 Clathrin_repeat [ SRS ] IPR000547 Clathrin_repeat [ EBI ]

Interpro IPR008941 TPR-like [ SRS ] IPR008941 TPR-like [ EBI ] CluSTr P53675 Pfam PF00637 Clathrin [ SRS ] PF00637 Clathrin [ Sanger ] pfam00637 [ NCBI- CDD ]

PF01394 Clathrin_propel [ SRS ] PF01394 Clathrin_propel [ Sanger Pfam ] pfam01394 [ NCBI-CDD ]

Smart SM00299 CLH [EMBL] Blocks P53675 Polymorphism : SNP, mutations, diseases OMIM 601273 [ map ] GENECLINICS 601273

SNP CLTCL1 [dbSNP-NCBI]

SNP NM_001835 [SNP-NCI]

SNP NM_007098 [SNP-NCI]

SNP CLTCL1 [GeneSNPs - Utah] CLTCL1 [SNP - CSHL] CLTCL1] [HGBASE - SRS] General knowledge Family CLTCL1 [UCSC Family Browser] Browser SOURCE NM_001835 SOURCE NM_007098 SMD Hs.368266 SAGE Hs.368266 Amigo function|binding Amigo component|clathrin vesicle coat Amigo component|coated pit Amigo process|morphogenesis Amigo process|receptor mediated endocytosis Amigo function|signal transducer activity PubGene CLTCL1 Other databases Probes Probe CLTCL1 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Structural domains of clathrin heavy chains. Kirchhausen T, Harrison SC J Cell Biol 1984; 99: 1725-1734.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -476- Medline 85030579

Characterization of a second human clathrin heavy chain polypeptide gene (CLH-22) from chromosome 22q11. Kedra D, Peyrard M, Fransson I, Collins JE, Dunham I, Roe BA, Dumanski JP. Hum Mol Genet 1996; 5: 625-631.

Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome. Sirotkin H, Morrow B, DasGupta R, Goldberg R, Patanjali SR, Shi G, Cannizzaro L, Shprintzen R, Weissman SM, Kucherlapati R. Hum Mol Genet 1996; 5: 617-624. Medline 96311556

Cloning and characterization of a novel human clathrin heavy chain gene (CLTCL). Long KR, Trofatter JA, Ramesh V, McCormick MK, Buckler AJ. Genomics 1996; 35: 466-472. Medline 97001147

Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation. Holmes SE, Riazi MA, Gong W, McDermid HE, Sellinger BT, Hua A, Chen F, Wang Z, Zhang G, Roe B, Gonzalez I, McDonald-McGinn DM, Zackai E, Emanuel BS, Budarf ML. Hum Mol Genet 1997; 6: 357-367. Medline 97227280

Clathrin-coated vesicle formation and protein sorting: an integrated process. Schmid SL. Annu Rev Biochem 1997, 66:511-548.

Clathrin. Kirchhausen T. Annu Rev Biochem 2000; 69: 699-727.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -477- Delsol G. Blood 2000; 95: 3204-3207.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Jean-Loup Huret 2001 Updated 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . CLTCL1 (clathrin heavy polypeptide-like 1). Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CLTCL1ID361.html Huret JL . CLTCL1 (clathrin heavy polypeptide-like 1). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CLTCL1ID361.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -478- Atlas of Genetics and Cytogenetics in Oncology and Haematology

LAF4 (lymphoid nuclear protein related to AF4)

Identity Other MLLT2-related protein, lymphoid nuclear protein 4 names Hugo LAF4 Location 2q11.2-2q12 DNA/RNA Description at least 17 exons. Transcription in a telomere to centromere direction; 3857 bp mRNA; 3684 bp open reading frame. Protein

Description 1227 amino acids; 133734 Da. Expression Preferentially expressed in lymphoid tissues, highest levels being found in the thymus. Lower expression in brain and lung. Localisation Nuclear Function Putative transcription activator that may function in lymphoid development and oncogenesis. Binds in vitro to double-stranded DNA Homology Belongs to the AF4/LAF4/FMR2/AF5q31 family. Implicated in Entity t(2;11)(q11;q23) . --> MLL-LAF4 Note MLL fusion partner at chromosome 2 in infant ALL Disease The three cases reported to date were all infant-ALL with proB phenotype Prognosis Prognosis is poor, although based on only three cases. Cytogenetics The three reported cases harboured different rearrangements involving chromosomes 2 and 11: t(2;11)(q11;q23), t(2;11)(p15;p14), and ins(11;2)(q23;q11.2q11.2). Abnormal The MLL-LAF4 fusion protein includes the transactivation domain of Protein LAF4 that is part of the AF4/LAF4/FMR2 homology domain.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -479-

Coding sequence of LAF4 compared to AF4 and site of fusion. Schematic representation of MLL, LAF4, AF4, and the putative MLL-LAF4 fusion protein. Domains in MLL are shaded: MT, DNA methyltransferase homology region; TRX, Drosophila trithorax homology. The percentage of amino acid homology between corresponding regions of LAF4 and AF4 is indicated: NHD, N-terminal homology domain; ALF, AF4/LAF4/FMR2 homology domain; TAD, transactivation domain; NLS, nuclear localization sequence; CHD, C-terminal homology domain. Arrows indicate the fusion sites with MLL. The breakpoint in LAF4 corresponds to one of the known breakpoints in AF4.

External links Nomenclature Hugo LAF4 GDB LAF4 Entrez_Gene LAF4 3899 lymphoid nuclear protein related to AF4 Cards Atlas LAF4ID315 GeneCards LAF4 Ensembl LAF4 CancerGene LAF4 Genatlas LAF4 GeneLynx LAF4 eGenome LAF4 euGene 3899 Genomic and cartography GoldenPath LAF4 - chr2:99626334-100179486 - 2q11.2 (hg17-May_2004) Ensembl LAF4 - 2q11.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene LAF4 Gene and transcription

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -480- Genbank AK092327 [ SRS ] AK092327 [ ENTREZ ]

Genbank BC036895 [ SRS ] BC036895 [ ENTREZ ]

Genbank U34360 [ SRS ] U34360 [ ENTREZ ]

RefSeq NM_002285 [ SRS ] NM_002285 [ ENTREZ ]

RefSeq NT_086620 [ SRS ] NT_086620 [ ENTREZ ] AceView LAF4 AceView - NCBI TRASER LAF4 Traser - Stanford

Unigene Hs.444414 [ SRS ] Hs.444414 [ NCBI ] HS444414 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P51826 [ SRS] P51826 [ EXPASY ] P51826 [ INTERPRO ]

Interpro IPR007797 AF-4 [ SRS ] IPR007797 AF-4 [ EBI ] CluSTr P51826

Pfam PF05110 AF-4 [ SRS ] PF05110 AF-4 [ Sanger ] pfam05110 [ NCBI-CDD ] Blocks P51826 Polymorphism : SNP, mutations, diseases OMIM 601464 [ map ] GENECLINICS 601464

SNP LAF4 [dbSNP-NCBI]

SNP NM_002285 [SNP-NCI]

SNP LAF4 [GeneSNPs - Utah] LAF4 [SNP - CSHL] LAF4] [HGBASE - SRS] General knowledge Family LAF4 [UCSC Family Browser] Browser SOURCE NM_002285 SMD Hs.444414 SAGE Hs.444414 Amigo function|DNA binding Amigo process|development Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent PubGene LAF4 Other databases Probes Probe LAF4 Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography LAF-4 encodes a lymphoid nuclear protein with transactivation potential that is

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -481- homologous to AF-4, the gene fused to MLL in t(4;11) leukemias. Ma C, Staudt LM. Blood 1996; 87(2): 734-745. Medline 8555498

LAF4, an AF4-related gene, is fused to MLL in infant acutelymphoblastic leukemia. von Bergh ARM, Beverloo HB, Rombout P, van Wering ER, van Weel MH, Beverstock GC, Kluin PM, Slater RM, Schuuring E. Genes Chromosomes Cancer 2002; 35 (1): 92-96. Medline 12203795

Occurrence of an MLL/LAF4 fusion gene caused by the insertion ins(11;2)(q23;q11.2q11.2) in an infant with acute lymphoblastic leukemia. Bruch J, Wilda M, Teigler-Schlegel A, Harbott J, Borkhardt A, Metzler M. Genes Chromosomes Cancer 2003; 37(1): 106-109. Medline 22546698

Fusion of an AF4-related gene, LAF4, to MLL in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23). Hiwatari M, Taki T, Taketani T, Taniwaki M, Sugita K, Okuya M, Eguchi M, Ida K, Hayashi Y. Oncogene 2003; 22(18): 2851-2855. Medline 12743608

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Anne RM von Bergh 2003 Citation This paper should be referenced as such : von Bergh ARM . LAF4 (lymphoid nuclear protein related to AF4). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/LAF4ID315.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -482- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MYH9 (myosin, heavy polypeptide 9, non-muscle)

Identity Other Myosin heavy chain, nonmuscle type A names Nonmuscle myosin heavy chain-A (NMMHC-A) Hugo MYH9 Location 22q12 DNA/RNA Description spans 107 kb; 40 exons Transcription alternate splicing; transcripts of 4.4, 5.3 and 5.9 kb Protein

Description 1960 amino acids; 227 kDa (and 1752 aa, 202 kDa, and 1486 aa, 172 kDa; globular head in N-term and a coiled-coil tail in C-term; actin binding site and light chains binding site are present in the globular domain. Myosin forms hexamers with 2 heavy chains, 2 essential (alkali) light chains, and 2 regulatory light chains Expression in platelets; upregulated during granulocyte differentiation (see below); also expressed in thymus, spleen, kidney, intestine, cochlea .... Function binds actin; protein of the cytoskeleton; role in cell shape and motility, and in cell division Mutations Germinal in autosomal dominant giant-platelet disorders Somatic in non Hodgkin lymphomas Implicated in Disease The autosomal dominant giant-platelet disorders, May-Hegglin anomaly (MHA), Fechtner syndrome (FTNS), and Sebastian syndrome (SBS), which share a triad of thrombocytopenia, large platelets (macrothrombocytopenia (MTCP)) and characteristic leukocyte inclusions (Dohle-like bodies), Epstein syndrome, which associates additional Alport-like clinical features (inherited sensorineural deafness, cataracts, nephritis), and MTCP without leukocyte inclusions, as well as a nonsyndromic hereditary hearing impairment are all caused by (germinal) mutations in MYH9. These disorders appear to represent a class of allelic disorders with variable phenotypic diversity. No clear no genotype-phenotype

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -483- correlation was identified

Entity Anaplasic large cell lymphoma (ALCL) with t(2;22)(p23;q12) --> ALK- CLTC Disease ALCL are high grade non Hodgkin lymphomas; ALK+ ALCL are ALCL where ALK is involved in a fusion gene; ALK+ ALCL represent 50 to 60 % of ALCL cases (they are CD30+, ALK+;); belong to the "cytoplasmic ALK+" subset. Prognosis Althouth presenting as a high grade tumour, a 80% five yr survival is associated with this anomaly Hybrid/Mutated 5' MYH9 - 3' ALK Gene Abnormal NH2 MYH9 - COOH ALK Protein

External links Nomenclature Hugo MYH9 GDB MYH9 Entrez_Gene MYH9 4627 myosin, heavy polypeptide 9, non-muscle Cards Atlas MYH9ID481 GeneCards MYH9 Ensembl MYH9 CancerGene MYH9 Genatlas MYH9 GeneLynx MYH9 eGenome MYH9 euGene 4627 Genomic and cartography MYH9 - 22q12 chr22:35001827-35108481 - 22q12.3 (hg17- GoldenPath May_2004) Ensembl MYH9 - 22q12.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MYH9 Gene and transcription

Genbank Z82215 [ SRS ] Z82215 [ ENTREZ ]

Genbank AB191263 [ SRS ] AB191263 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -484- Genbank AK025219 [ SRS ] AK025219 [ ENTREZ ]

Genbank AK025393 [ SRS ] AK025393 [ ENTREZ ]

Genbank AK131080 [ SRS ] AK131080 [ ENTREZ ]

RefSeq NM_002473 [ SRS ] NM_002473 [ ENTREZ ]

RefSeq NT_086921 [ SRS ] NT_086921 [ ENTREZ ] AceView MYH9 AceView - NCBI TRASER MYH9 Traser - Stanford

Unigene Hs.474751 [ SRS ] Hs.474751 [ NCBI ] HS474751 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P35579 [ SRS] P35579 [ EXPASY ] P35579 [ INTERPRO ]

Prosite PS50096 IQ [ SRS ] PS50096 IQ [ Expasy ]

Interpro IPR000048 IQ_region [ SRS ] IPR000048 IQ_region [ EBI ]

Interpro IPR001609 Myosin_head [ SRS ] IPR001609 Myosin_head [ EBI ]

Interpro IPR004009 Myosin_N [ SRS ] IPR004009 Myosin_N [ EBI ]

Interpro IPR002928 Myosin_tail [ SRS ] IPR002928 Myosin_tail [ EBI ]

Interpro IPR002017 Spectrin [ SRS ] IPR002017 Spectrin [ EBI ] CluSTr P35579

Pfam PF00612 IQ [ SRS ] PF00612 IQ [ Sanger ] pfam00612 [ NCBI-CDD ]

PF00063 Myosin_head [ SRS ] PF00063 Myosin_head [ Sanger Pfam ] pfam00063 [ NCBI-CDD ] Pfam PF02736 Myosin_N [ SRS ] PF02736 Myosin_N [ Sanger ] pfam02736 [ NCBI-CDD ]

PF01576 Myosin_tail_1 [ SRS ] PF01576 Myosin_tail_1 [ Sanger Pfam ] pfam01576 [ NCBI-CDD ]

Prodom PD000355 Myosin_head[INRA-Toulouse] Prodom P35579 MYH9_HUMAN [ Domain structure ] P35579 MYH9_HUMAN [ sequences sharing at least 1 domain ] Blocks P35579 Polymorphism : SNP, mutations, diseases OMIM 160775 [ map ] GENECLINICS 160775

SNP MYH9 [dbSNP-NCBI]

SNP NM_002473 [SNP-NCI]

SNP MYH9 [GeneSNPs - Utah] MYH9 [SNP - CSHL] MYH9] [HGBASE - SRS] General knowledge Family MYH9 [UCSC Family Browser] Browser SOURCE NM_002473 SMD Hs.474751 SAGE Hs.474751

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -485- Amigo function|ATP binding Amigo function|actin binding Amigo function|calmodulin binding Amigo process|cellular morphogenesis Amigo function|motor activity Amigo function|motor activity Amigo component|myosin Amigo component|non-muscle myosin Amigo process|perception of sound PubGene MYH9 Other databases Probes Probe MYH9 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, Ghiggeri GM, Ravazzolo R, Savino M, Del Vecchio M, d'Apolito M, Iolascon A, Zelante LL, Savoia A, Balduini CL, Noris P, Magrini U, Belletti S, Heath KE, Babcock M, Glucksman MJ, Aliprandis E, Bizzaro N, Desnick RJ, Martignetti JA. Nat Genet. 2000; 26: 103-105. Medline 10973259

Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Kelley MJ, Jawien W, Ortel TL, Korczak JF. Nat Genet. 2000; 26:106-108. Medline 10973260

Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN. Am J Hum Genet. 2000; 67: 1121-1128. Medline 11023810

Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. Kunishima S, Matsushita T, Kojima T, Amemiya N, Choi YM, Hosaka N, Inoue M, Jung Y, Mamiya S, Matsumoto K, Miyajima Y, Zhang G, Ruan C, Saito K, Song KS, Yoon HJ, Kamiya T, Saito H.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -486- J Hum Genet. 2001; 46: 722-729. Medline 11776386

Five (un)easy pieces: the MYH9-related giant platelet syndromes. Martignetti J. Haematologica. 2002; 87: 897-898. Medline 12217798

MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A. Medicine (Baltimore). 2003; 82: 203-215. Medline 12792306

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . MYH9 (myosin, heavy polypeptide 9, non-muscle). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MYH9ID481.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -487- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RANBP2 (RAN binding protein)

Identity Other NUP358 (nucleoporin 358 kDa) names Location 2q13 Protein

Description 3224 amino acids, 358 kDa; is composed, from N-term to C-term, of: a leucine -rich region with a leucine zipper, 4 RAN-binding domains, , 8 Zn fingers, and an internal repeat region Function nuclear export transporter; bind RAN-GTP and exportin-1 Implicated in Entity Inflammatory myofibroblastic tumors with t(2;2)(p23;q13) Disease rare soft tissue tumour found in children and young adults Prognosis good prognosis Hybrid/Mutated 5' RANBP2 - 3' ALK Gene External links Nomenclature GDB RANBP2 Entrez_Gene RANBP2 5903 RAN binding protein 2 Cards Atlas RANBP2ID483 GeneCards RANBP2 Ensembl RANBP2 CancerGene RANBP2 Genatlas RANBP2 GeneLynx RANBP2 eGenome RANBP2 euGene 5903 Genomic and cartography RANBP2 - 2q13 chr2:108794455-108859768 + 2q13 (hg17- GoldenPath May_2004)

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -488- Ensembl RANBP2 - 2q13 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RANBP2 Gene and transcription

Genbank L41840 [ SRS ] L41840 [ ENTREZ ]

Genbank AA971491 [ SRS ] AA971491 [ ENTREZ ]

Genbank AK025462 [ SRS ] AK025462 [ ENTREZ ]

Genbank AK025711 [ SRS ] AK025711 [ ENTREZ ]

Genbank AK026993 [ SRS ] AK026993 [ ENTREZ ]

RefSeq NM_006267 [ SRS ] NM_006267 [ ENTREZ ]

RefSeq NT_086621 [ SRS ] NT_086621 [ ENTREZ ] AceView RANBP2 AceView - NCBI TRASER RANBP2 Traser - Stanford

Unigene Hs.199561 [ SRS ] Hs.199561 [ NCBI ] HS199561 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P49792 [ SRS] P49792 [ EXPASY ] P49792 [ INTERPRO ]

Prosite PS00170 CSA_PPIASE_1 [ SRS ] PS00170 CSA_PPIASE_1 [ Expasy ]

Prosite PS50072 CSA_PPIASE_2 [ SRS ] PS50072 CSA_PPIASE_2 [ Expasy ]

Prosite PS50196 RANBD1 [ SRS ] PS50196 RANBD1 [ Expasy ]

Prosite PS50005 TPR [ SRS ] PS50005 TPR [ Expasy ]

Prosite PS50293 TPR_REGION [ SRS ] PS50293 TPR_REGION [ Expasy ]

Prosite PS01358 ZF_RANBP2_1 [ SRS ] PS01358 ZF_RANBP2_1 [ Expasy ]

Prosite PS50199 ZF_RANBP2_2 [ SRS ] PS50199 ZF_RANBP2_2 [ Expasy ]

Interpro IPR002130 CSA_PPIase [ SRS ] IPR002130 CSA_PPIase [ EBI ]

Interpro IPR000697 EVH1 [ SRS ] IPR000697 EVH1 [ EBI ]

Interpro IPR011036 PH_related [ SRS ] IPR011036 PH_related [ EBI ]

Interpro IPR000156 Ran_BP1 [ SRS ] IPR000156 Ran_BP1 [ EBI ]

Interpro IPR001440 TPR [ SRS ] IPR001440 TPR [ EBI ]

Interpro IPR008941 TPR-like [ SRS ] IPR008941 TPR-like [ EBI ]

Interpro IPR001876 Znf_RanGDP [ SRS ] IPR001876 Znf_RanGDP [ EBI ] CluSTr P49792

PF00160 Pro_isomerase [ SRS ] PF00160 Pro_isomerase [ Sanger Pfam ] pfam00160 [ NCBI-CDD ] Pfam PF00638 Ran_BP1 [ SRS ] PF00638 Ran_BP1 [ Sanger ] pfam00638 [ NCBI-CDD ]

Pfam PF00515 TPR [ SRS ] PF00515 TPR [ Sanger ] pfam00515 [ NCBI-CDD ] Pfam PF00641 zf-RanBP [ SRS ] PF00641 zf-RanBP [ Sanger ] pfam00641 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -489- Smart SM00160 RanBD [EMBL]

Smart SM00547 ZnF_RBZ [EMBL] Blocks P49792

PDB 1RRP [ SRS ] 1RRP [ PdbSum ], 1RRP [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 601181 [ map ] GENECLINICS 601181

SNP RANBP2 [dbSNP-NCBI]

SNP NM_006267 [SNP-NCI]

SNP RANBP2 [GeneSNPs - Utah] RANBP2 [SNP - CSHL] RANBP2] [HGBASE - SRS] General knowledge Family RANBP2 [UCSC Family Browser] Browser SOURCE NM_006267 SMD Hs.199561 SAGE Hs.199561 Amigo function|RAN protein binding Amigo function|binding Amigo function|isomerase activity Amigo component|nuclear pore Amigo component|nucleus Amigo function|peptidyl-prolyl cis-trans isomerase activity Amigo process|protein folding Amigo process|protein-nucleus import Amigo process|transport BIOCARTA Mechanism of Protein Import into the Nucleus BIOCARTA Cycling of Ran in nucleocytoplasmic transport BIOCARTA Sumoylation by RanBP2 Regulates Transcriptional Repression PubGene RANBP2 Other databases Probes PubMed PubMed 14 Pubmed reference(s) in LocusLink Bibliography A giant nucleopore protein that binds Ran/TC4. Yokoyama N, Hayashi N, Seki T, Pante N, Ohba T, Nishii K, Kuma K, Hayashida T, Miyata T, Aebi U, et al. Nature. 1995; 376: 184-188. Medline 7603572

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -490-

A small ubiquitin related polypeptide involved in targeting Ran-GAP1 to nuclear pore complex protein RANBP2. Mahajan R, Delphin C, Guan T, Gerance L, Melchior F. Cell 1997; 88: 97-107. Medline PMID:

Identification of a novel Ran binding protein 2 related gene (RANBP2L1) and detection of a gene cluster on human chromosome 2q11-q12. Nothwang HG, Rensing C, Kubler M, Denich D, Brandl B, Stubanus M, Haaf T, Kurnit D, Hildebrandt F. Genomics. 1998; 47: 383-392. Medline 9480752

Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Vetter IR, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A. Nature. 1999; 398: 39-46. Medline 10078529

GTP hydrolysis links initiation and termination of nuclear import on the nucleoporin nup358. Yaseen NR, Blobel G. J Biol Chem. 1999; 274: 26493-26502. Medline 10473610

Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor. Ma Z, Hill DA, Collins MH, Morris SW, Sumegi J, Zhou M, Zuppan C, Bridge JA. Genes Chromosomes Cancer 2003; 37: 98-105. Medline 12661011 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . RANBP2 (RAN binding protein). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RANBP2ID483.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -491-

Atlas of Genetics and Cytogenetics in Oncology and Haematology

REG-IV (regenerating gene type IV)

Identity Location 1p12 DNA/RNA Description the gene spans 17 kb; 1191 bp cDNA; 6 exons; ORF: 474 bp Protein

Description 158 amino acids, 18 kDa. Expression gastrointestinal tract: stomach, small intestine, colon, and pancreas. High expression inCrohn's disease and in ulcerative colitis. Function supposed to be involved in cell regeneration and/ or survival Homology with other members of the REG family, of which are PSP/REG-I alpha and PAP Mutations Somatic strongly expressed in colorectal tumors as compared to normal colon tissue. External links Nomenclature GDB REG4 Entrez_Gene REG4 83998 regenerating islet-derived family, member 4 Cards Atlas REGIVID485 GeneCards REG4 Ensembl REG4 CancerGene REG4 Genatlas REG4 GeneLynx REG4 eGenome REG4 euGene 83998 Genomic and cartography REG4 - 1p12 chr1:120048751-120066245 - 1p12 (hg17- GoldenPath May_2004)

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -492- Ensembl REG4 - 1p12 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene REG4 Gene and transcription

Genbank AL359752 [ SRS ] AL359752 [ ENTREZ ]

Genbank AF254415 [ SRS ] AF254415 [ ENTREZ ]

Genbank AF345934 [ SRS ] AF345934 [ ENTREZ ]

Genbank AK057107 [ SRS ] AK057107 [ ENTREZ ]

Genbank AY007243 [ SRS ] AY007243 [ ENTREZ ]

RefSeq NM_032044 [ SRS ] NM_032044 [ ENTREZ ]

RefSeq NT_086588 [ SRS ] NT_086588 [ ENTREZ ] AceView REG4 AceView - NCBI TRASER REG4 Traser - Stanford

Unigene Hs.171480 [ SRS ] Hs.171480 [ NCBI ] HS171480 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9BYZ8 [ SRS] Q9BYZ8 [ EXPASY ] Q9BYZ8 [ INTERPRO ] Prosite PS00615 C_TYPE_LECTIN_1 [ SRS ] PS00615 C_TYPE_LECTIN_1 [ Expasy ] Prosite PS50041 C_TYPE_LECTIN_2 [ SRS ] PS50041 C_TYPE_LECTIN_2 [ Expasy ]

Interpro IPR001304 Lectin_C [ SRS ] IPR001304 Lectin_C [ EBI ]

Interpro IPR003990 Pancreatis_ac [ SRS ] IPR003990 Pancreatis_ac [ EBI ] CluSTr Q9BYZ8 Pfam PF00059 Lectin_C [ SRS ] PF00059 Lectin_C [ Sanger ] pfam00059 [ NCBI- CDD ]

Smart SM00034 CLECT [EMBL] Blocks Q9BYZ8 Polymorphism : SNP, mutations, diseases

SNP REG4 [dbSNP-NCBI]

SNP NM_032044 [SNP-NCI]

SNP REG4 [GeneSNPs - Utah] REG4 [SNP - CSHL] REG4] [HGBASE - SRS] General knowledge Family REG4 [UCSC Family Browser] Browser SOURCE NM_032044 SMD Hs.171480 SAGE Hs.171480 Amigo function|sugar binding PubGene REG4 Other databases

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -493- Probes PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Hartupee JC, Zhang H, Bonaldo MF, Soares MB, Dieckgraefe BK. Biochim Biophys Acta. 2001; 1518: 287-293. Medline 11311942

Reg IV, a new member of the regenerating gene family, is overexpressed in colorectal carcinomas. Violette S, Festor E, Pandrea-Vasile I, Mitchell V, Adida C, Dussaulx E, Lacorte JM, Chambaz J, Lacasa M, Lesuffleur T. Int J Cancer. 2003; 103: 185-193. Medline 12455032

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . REG-IV (regenerating gene type IV). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/REGIVID485.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -494- Atlas of Genetics and Cytogenetics in Oncology and Haematology

IGH (Immunoglobulin Heavy)

Identity Note The human IGH locus is located on the chromosome 14 at band 14q32.33, at the telomeric extremity of the long arm; the orientation of the locus has been determined by the analysis of translocations, involving the IGH locus, in leukemia and lymphoma Hugo IGH@ Location 14q32.33

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -495-

IGH V-GENE: Green box: Functional; Yellow box: Open reading frame; Red: Pseudogene; Grey triangle: Not sequenced, not found. D-GENE: Blue: Functional; Blue open box: Open reading frame. J-GENE: Grey: Functional . C-GENE: Blue: Functional; Blue dashed box: Open reading frame; Blue open box: Pseudogene. GENES NOT RELATED: Purple open box: Pseudogene. for compete Figure, see: locus IGH, IMGT (The International ImMunoGeneTics information system ®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human IGH locus at 14q32.33 spans 1250 kilobases (kb). It consists of 123 to 129 IGHV genes, depending from the haplotypes, 27

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -496- IGHD segments belonging to 7 subgroups, 9 IGHJ segments, and 11 IGHC genes. Eighty-two to 88 IGHV genes belong to 7 subgroups, whereas 41 pseudogenes, which are too divergent to be assigned to subgroups, have been assigned to 4 clans. Seven non-mapped IGHV genes have been described as insertion/deletion polymorphism but have not yet been precisely located. The most 5' IGHV genes occupy a position very close to the chromosome 14q telomere whereas the IGHC genes are in a more centromeric position. The potentiel genomic IGH repertoire is more limited since it comprises 38-46 functional IGHV genes belonging to 6 or 7 subgroups depending from the haplotypes 23 IGHD, 6 IGHJ, and 9 IGHC genes. Thirty-five IGH genes have been found outside the main locus in other chromosomal localizations. These genes designated as orphons cannot contribute to the synthesis of the immunoglobulin chains, even if they have an Open Reading Frame (ORF). 9 IGHV orphons and 10 IGHD orphons have been described on chromosome 15 (15q11.2), and 16 IGHV orphons on chromosome 16 (16p11.2). In addition, one IGHC processed gene, IGHEP2 is localised on chromosome 9 (9p24.2-p24.1) This is so far the only processed Ig gene described. The total number of human IGH genes per haploid genome is 170 to 176 (206 to 212 genes, if the orphons and the processed gene are included) of which 77 to 84 genes are functional. List of the human IGH genes Protein

Description Proteins encoded by the IGH locus are the immunoglobulin heavy chains. They result from the recombination (or rearrangement), at the DNA level, of three genes: IGHV, IGHD and IGHJ, with deletion of the intermediary DNA to create a rearranged IGHV-D-J gene. The rearranged IGHV-D-J gene is transcribed with the IGHM gene and translated into an immunoglobulin mu chain. The gamma, alpha or epsilon heavy chains, result from a new recombination (or switch), again at the DNA level, between sequences designated as "Switch" and localized upstream of the IGHM and of each of the functional IGHG, IGHA and IGHE constant genes. This recombination, accompanied by the deletion of the intermediary DNA, allows the IGHV-D-J initially transcribed with the IGHM, to be now transcribed with a IGHG, IGHA or IGHE gene, and translated into a gamma, alpha or epsilon chain. Translation of the variable germline genes involved in the IGHV-D-J rearrangements are available at IMGT Repertoire Protein displays. Compared to the germline genes, the rearranged variable genes will acquire somatic mutations during the B cell differentiation in the lymph nodes, which will considerably increase their diversity. These somatic mutations can be analysed using IMGT/V-QUEST tool Mutations

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -497- Note Mutations which correspond to allelic polymorphisms of the functional germline IGHV, IGHD, IGHJ and IGHC genes are described in the IMGT database: (IMGT Repertoire>Alignments of alleles) Implicated in Entity Translocations which frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements, or from errors of the switch enzyme. IGHV, IGHD or IGHJ recombination signals or isolated heptamer (first case) or switch sequences (second case) are observed at the breakpoints

c-Immunoglobulin genes IgH at 14q32.33, in normal cells: PAC 998D24 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi

Entity t(1;14)(p21;q32); involve BCL10 in 1p21 Disease marginal zone B-cell lymphoma

Entity t(3;14)(q27;q32); involve BCL6 in 3q27 Disease B-cell non-Hodgkin lymphomas (NHL), mainly diffuse large cell lymphoma; adult aggressive lymphoma Prognosis controversial

Entity t(4;14)(p16;q32); involve FGFR3 in 4p16 Disease plasma cell leukaemia and multiple myeloma Prognosis yet poorly described

Entity t(5;14)(q31;q32); involve IL3 in 5q31 Disease B-cell acute lymphoblastic leukemia (ALL) with hypereosinophilia Prognosis prognosis appears to be poor

Entity t(8;14)(q11;q32) Disease B-cell acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia (CML) Prognosis still unknown

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -498-

Entity t(8;14)(q24;q32) ; involve C-MYC in 8q24 Disease B-cell acute lymphoblastic leukemia (ALL3) and non-Hodgkin lymphomas (NHL), especially in the Burkitt lymphoma Prognosis the prognosis has evolved with new treatments

Entity t(9;14)(p13;q32); involve PAX5 in 9p13 Disease lymphoplasmatic lymphoma

Entity t(10;14)(q24;q32); involve HOX 11 in 10q24 Disease B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) Prognosis not unfavourable

Entity t(11;14)(q13;q32); involve BCL1 in 11q13 Disease t(11;14) is mainly found in mantle cell lymphoma; B-prolymphocytic leukaemia, chronic lymphocytic leukaemia, splenic lymphoma with villous lymphocytes , and multiple myeloma other B-cell lymphoproliferations

Entity t(14;18)(q32;q21); involve BCL2 in 18q21 Disease follicle centre cell lymphoma mainly, and also diffuse large cell lyphoma; rarely in other B-cell lymphoproliferations Prognosis the t(14;18) may have little or no prognostic significance

Entity t(14;19)(q32;q13.1); involve BCL3 in 19q13 Disease chronic lymphocytic leukaemia (CLL) mainly, and other B-cell lymphoproliferations Prognosis t(14;19) is an adverse prognostic factor in CLL, compared to the usual prognosis in CLL

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -499-

External links Nomenclature Hugo IGH@ GDB IGH@ Entrez_Gene IGH@ 3492 immunoglobulin heavy locus Cards Atlas IgHID40 GeneCards IGH@ Ensembl IGH@ Genatlas IGH@ GeneLynx IGH@ eGenome IGH@ euGene 3492 Genomic and cartography GoldenPath IGH@ - 14q32.33 Ensembl IGH@ - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene IGH@ Gene and transcription

Genbank AB019437 [ SRS ] AB019437 [ ENTREZ ]

Genbank AB019438 [ SRS ] AB019438 [ ENTREZ ]

Genbank AB019439 [ SRS ] AB019439 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -500- Genbank AB019440 [ SRS ] AB019440 [ ENTREZ ]

Genbank AB019441 [ SRS ] AB019441 [ ENTREZ ] AceView IGH@ AceView - NCBI TRASER IGH@ Traser - Stanford

Unigene Hs.525646 [ SRS ] Hs.525646 [ NCBI ] HS525646 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases

SNP IGH@ [dbSNP-NCBI]

SNP IGH@ [GeneSNPs - Utah] IGH@ [SNP - CSHL] IGH@] [HGBASE - SRS] General knowledge Family IGH@ [UCSC Family Browser] Browser SMD Hs.525646 SAGE Hs.525646 PubGene IGH@ Other databases Other IGH@ - IMGT database Probes Probe Probes IMGT Probe Immunoglobulin genes IgH at14q32.33, in normal cells (Bari) Probe IGH@ Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography Chromosomal location of the genes for human immunoglobulin heavy chains. Croce CM, Shander M, Martinis J, Cicurel L, D'Ancona GG, Dolby TW, Koprowski H. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3416-9. Medline 114999

Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. Kirsch IR, Morton CC, Nakahara K, Leder P. Science. 1982 Apr 16;216(4543):301-3. No abstract available. Medline 6801764

Localization of human variable and constant region immunoglobulin heavy chain genes on subtelomeric band q32 of chromosome 14. McBride OW, Battey J, Hollis GF, Swan DC, Siebenlist U, Leder P. Nucleic Acids Res. 1982 Dec 20;10(24):8155-70. Medline 6819544

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -501-

Physical map of the 3' region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype. Shin EK, Matsuda F, Nagaoka H, Fukita Y, Imai T, Yokoyama K, Soeda E, Honjo T. EMBO J. 1991 Dec;10(12):3641-5. Medline 1935893

A map of the human immunoglobulin VH locus completed by analysis of the telomeric region of chromosome 14q. Cook GP, Tomlinson IM, Walter G, Riethman H, Carter NP, Buluwela L, Winter G, Rabbitts TH. Nat Genet. 1994 Jun;7(2):162-8. Medline 7920635

The human immunoglobulin VH repertoire. Cook GP, Tomlinson IM. Immunol Today. 1995 May;16(5):237-42. Review. Medline 7779254

The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. Matsuda F, Ishii K, Bourvagnet P, Kuma Ki, Hayashida H, Miyata T, Honjo T. J Exp Med. 1998 Dec 7;188(11):2151-62. Medline 9841928

Organization of human immunoglobulin heavy chain diversity gene loci. Ichihara Y, Matsuoka H, Kurosawa Y. EMBO J. 1988 Dec 20;7(13):4141-50. Medline 3243276

The human immunoglobulin heavy variable genes. Pallares N, Lefebvre S, Contet V, Matsuda F, Lefranc M. Exp Clin Immunogenet. 1999;16(1):36-60. Review. Medline 10087405

The use of chromosomal translocations to study human immunoglobulin gene organization: mapping DH segments within 35 kb of the C mu gene and identification of a new DH locus. Buluwela L, Albertson DG, Sherrington P, Rabbitts PH, Spurr N, Rabbitts TH. EMBO J. 1988 Jul;7(7):2003-10. Medline 3138112

Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, "minor" D segments or D-D recombination. Corbett SJ, Tomlinson IM, Sonnhammer ELL, Buck D, Winter G.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -502- J Mol Biol. 1997 Jul 25;270(4):587-97. Medline 9245589

The human immunoglobulin heavy diversity (IGHD) and joining (IGHJ) segments. Ruiz M, Pallares N, Contet V, Barbi V, Lefranc M. Exp Clin Immunogenet. 1999;16(3):173-84. Medline 10394055

Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Ravetch JV, Siebenlist U, Korsmeyer S, Waldmann T, Leder P. Cell. 1981 Dec;27(3 Pt 2):583-91. Medline 6101209

The sequence of a human immunoglobulin epsilon heavy chain constant region gene, and evidence for three non-allelic genes. Flanagan JG, Rabbitts TH. EMBO J. 1982;1(5):655-60. Medline 6234164

Instability of the human immunoglobulin heavy chain constant region locus indicated by different inherited chromosomal deletions. Lefranc MP, Lefranc G, de Lange G, Out TA, van den Broek PJ, van Nieuwkoop J, Radl J, Helal AN, Chaabani H, van Loghem E, et al. Mol Biol Med. 1983 Sep;1(2):207-17. Medline 6438434

Human immunoglobulin heavy chain genes: evolutionary comparisons of C mu, C delta and C gamma genes and associated switch sequences. Rabbitts TH, Forster A, Milstein CP. Nucleic Acids Res. 1981 Sep 25;9(18):4509-24. Medline 6795593

Human immunoglobulin D: genomic sequence of the delta heavy chain. White MB, Shen AL, Word CJ, Tucker PW, Blattner FR. Science. 1985 May 10;228(4700):733-7. Medline 3922054

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -503- Sequence of a human immunoglobulin gamma 3 heavy chain constant region gene: comparison with the other human C gamma genes. Huck S, Fort P, Crawford DH, Lefranc MP, Lefranc G. Nucleic Acids Res. 1986 Feb 25;14(4):1779-89. Medline 3081877

A human immunoglobulin IGHG3 allele (Gmb0,b1,c3,c5,u) with an IGHG4 converted region and three hinge exons. Huck S, Lefranc G, Lefranc MP. Immunogenetics. 1989;30(4):250-7. Medline 2571587

Ellison JW, Berson BJ, Hood LE. The nucleotide sequence of a human immunoglobulin C gamma1 gene. Nucleic Acids Res. 1982 Jul 10;10(13):4071-9. Medline 6287432

Duplication and deletion in the human immunoglobulin epsilon genes. Max EE, Battey J, Ney R, Kirsch IR, Leder P. Cell. 1982 Jun;29(2):691-9. Medline 6288268

Bensmana M, Huck S, Lefranc G, Lefranc MP. The human immunoglobulin pseudo-gamma IGHGP gene shows no major structural defect. Nucleic Acids Res. 1988 Apr 11;16(7):3108. No abstract available. Medline 3130612

Linkage and sequence homology of two human immunoglobulin gamma heavy chain constant region genes. Ellison J, Hood L. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1984-8. Medline 6804948

Nucleotide sequence of a human immunoglobulin C gamma 4 gene. Ellison J, Buxbaum J, Hood L. DNA. 1981;1(1):11-8. Medline 6299662

Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing gamma, epsilon and alpha genes. Flanagan JG, Rabbitts TH. Nature. 1982 Dec 23;300(5894):709-13. Medline 6817141

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -504- Sequence of the CH1 and hinge-CH2 exons of the human immunoglobulin IGHA2 A2m(2) allele: comparison with the nonallelic and allelic IGHA genes. Bensmana M, Chuchana P, Lefranc G, Lefranc MP. Cytogenet Cell Genet. 1991;56(2):128. Medline 1901541

Protein displays of the human immunoglobulin heavy, kappa and lambda variable and joining regions. Scaviner D, Barbie V, Ruiz M, Lefranc MP. Exp Clin Immunogenet. 1999;16(4):234-40. Medline 10575277

A processed human immunoglobulin epsilon gene has moved to chromosome 9. Battey J, Max EE, McBride WO, Swan D, Leder P. Proc Natl Acad Sci U S A. 1982 Oct;79(19):5956-60. Medline 6964396

Nomenclature of the human immunoglobulin genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1P.1-A.1P.37.

The Immunoglobulin FactsBook (Review) Lefranc M-P. and Lefranc G. Academic Press, London, UK (458 pages), 2001, ISBN:012441351X

Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P. The immunologist, 2000, 8,80-88.

Nomenclature of the human immunoglobulin heavy (IGH) genes (Review) Lefranc M.-P. Exp Clin Immunogenet. 2001;18(2):100-16. Medline 11340299

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -505- 2003 Citation This paper should be referenced as such : Lefranc MP . IGH (Immunoglobulin Heavy). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IgHID40.html Lefranc MP . IGH (Immunoglobulin Heavy). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IgHID40.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -506- Atlas of Genetics and Cytogenetics in Oncology and Haematology

IGK (Immunoglobulin Kappa)

Identity Note The human IGK locus is located on chromosome 2 on the short arm, at band 2p12. The orientation of the locus has been determined by the analysis of translocations, involving the IGK locus, in leukemia and lymphoma. Hugo IGK@ Location 2p12

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -507-

IGK V-GENE: Green box: Functional; Yellow box: Open reading frame; Red: Pseudogene. J-GENE: Grey: Functional . C-GENE: Blue: Functional. for complete Figure, see: locus IGK, IMGT (The International ImMunoGeneTics information system ®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human IGK locus at 2p12 spans 1820 kb. It consists of 76 IGKV genes belonging to 7 subgroups, 5 IGKJ segments, and a unique IGKC gene The 76 IGKV genes are organized in two clusters separated by 800 kb. The IGKV distal cluster (the most 5' from IGKC and in the most centromeric position) spans 400 kb and comprises 36 genes. The IGKV proximal cluster (in 3' of the locus, closer to IGKC, and in the most telomeric position) spans 600 kb and comprises 40 genes. The potential genomic IGK repertoire comprises 31 to 35 functional IGKV genes belonging to 5 subgroups, the 5 IGKJ segments, and the unique IGKC gene. One rare IGKV haplotype has been described which contains only the proximal cluster. This haplotype comprises the 40 proximal IGKV genes belonging to 7 subgroups, of which 17 to 19 are functional and belong to 5 subgroups. Twenty-eight IGKV orphons have been identified and sequenced: 3 on the short arm of chromosome 2 but outside of the main IGK locus, 13 on the long arm of chromosome 2, 6 on chromosome 22, one on chromosome 1, one on chromosome 15, and 4 outside of chromosome 2 If both the proximal and distal IGKV clusters are present, the total number of human IGK genes per haploid genome is 82 (110 genes, if the

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -508- orphons are included) of which 37-41 are functional. If only the proximal IGKV cluster is present, the total number of genes per haploid genome is 46 (74 genes, if the orphons are included) of which 23-25 genes are functional. List of the human IGK genes Protein

Description Proteins encoded by the IGK locus are the immunoglobulin kappa chains. They result from the recombination (or rearrangement), at the DNA level, of two genes: IGKV and IGKJ, with deletion of the intermediary DNA to create a rearranged IGKV-J gene. The rearranged IGKV-J gene is transcribed with the IGKC gene and translated into an immunoglobulin kappa chain. Translation of the variable germline genes involved in the IGKV-J rearrangements are available at IMGT Repertoire Protein displays. Compared to the germline genes, the rearranged variable genes will acquire somatic mutations during the B cell differentiation in the lymph nodes, which will considerably increase their diversity. These somatic mutations can be analysed using IMGT/V-QUEST tool Mutations Note Mutations which correspond to allelic polymorphisms of the functional germline IGKV, IGKJ and IGKC genes are described in the IMGT database: (IMGT Repertoire> Alignments of alleles) Implicated in Entity Translocations which frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), which is responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements. IGKV or IGKJ recombination signals or isolated heptamer are observed at the breakpoints

c-Immunoglobulin genes IgK at 2p12, in normal cells: PAC 1117G4 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi

Entity t(2;3;)(p12;q27); involve BCL6 in 3q27 Disease B-cell non-Hodgkin lymphomas (NHL), mainly diffuse large cell

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -509- lymphoma; adult aggressive lymphoma Prognosis controversial

Entity t(2;8)(p12;q24); involve C-MYC in 8q24 Disease B-cell acute lymphoblastic leukemia (ALL3) and non-Hodgkin lymphomas (NHL), especially in the Burkitt lymphoma Prognosis the prognosis has evolved with new treatments

Breakpoints

External links Nomenclature Hugo IGK@ GDB IGK@ Entrez_Gene IGK@ 50802 immunoglobulin kappa locus Cards Atlas IgKID17 GeneCards IGK@ Ensembl IGK@ Genatlas IGK@ GeneLynx IGK@ eGenome IGK@ euGene 50802 Genomic and cartography GoldenPath IGK@ - 2p12 Ensembl IGK@ - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI]

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -510- HomoloGene IGK@ Gene and transcription

Genbank - [ SRS ] - [ ENTREZ ] AceView IGK@ AceView - NCBI TRASER IGK@ Traser - Stanford Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases

SNP IGK@ [dbSNP-NCBI]

SNP IGK@ [GeneSNPs - Utah] IGK@ [SNP - CSHL] IGK@] [HGBASE - SRS] General knowledge Family IGK@ [UCSC Family Browser] Browser PubGene IGK@ Other databases Other IGK@ - IMGT database Probes Probe Immunoglobulin genes IgK at 2p12, in normal cells (Bari) Probe Probes IMGT Probe IGK@ Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Localization of human immunoglobulin kappa light chain variable region genes to the short arm of chromosome 2 by in situ hybridization. Malcolm S, Barton P, Murphy C, Ferguson-Smith MA, Bentley DL, Rabbitts TH. Proc Natl Acad Sci U S A. 1982 Aug;79(16):4957-61. Medline 6812058

The immunoglobulin kappa locus-or-what has been learned from looking closely at one-tenth of a percent of the human genome. Zachau HG. Gene. 1993 Dec 15;135(1-2):167-73. Review. Medline 8276255

The V kappa genes of the L regions and the repertoire of V kappa gene sequences in the human germ line Huber C, Schable KF, Huber E, Klein R, Meindl A, Thiebe R, Lamm R, Zachau HG. Eur J Immunol. 1993 Nov;23(11):2868-75 Medline 8223863

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -511- A directory of human germ-line V kappa segments reveals a strong bias in their usage. Cox JP, Tomlinson IM, Winter G. Eur J Immunol. 1994 Apr;24(4):827-36. Medline 8149953

The human immunoglobulin kappa locus: pseudogenes, unique and repetitive sequences. Schable K, Thiebe R, Flugel A, Meindl A, Zachau HG. Biol Chem Hoppe Seyler. 1994 Mar;375(3):189-99. Medline 8011175

The human immunoglobulin kappa variable (IGKV) genes and joining (IGKJ) segments. Barbie V, Lefranc MP. Exp Clin Immunogenet. 1998;15(3):171-83 Medline 9813414

Protein displays of the human immunoglobulin heavy, kappa and lambda variable and joining regions. Scaviner D, Barbie V, Ruiz M, Lefranc MP. Exp Clin Immunogenet. 1999;16(4):234-40 Medline 10575277

Evolution of human immunoglobulin kappa J region genes Hieter PA, Maizel JV Jr, Leder P. J Biol Chem. 1982 Feb 10;257(3):1516-22. Medline 6276389

Evolution of human immunoglobulin kappa J region genes. Hieter PA, Maizel JV Jr, Leder P. J Biol Chem. 1982 Feb 10;257(3):1516-22. Medline 6276389

Cloned human and mouse kappa immunoglobulin constant and J region genes conserve homology in functional segments Hieter PA, Max EE, Seidman JG, Maizel JV Jr, Leder P. Cell. 1980 Nov;22(1 Pt 1):197-207. Medline 6775818

Nomenclature of the human immunoglobulin genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1P.1-A.1P.37.

The Immunologist FactsBook (Review)

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -512- Lefranc M-P. and Lefranc G. Academic Press, London, UK (458 pages), 2001, ISBN:012441351X

Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P. The immunologist, 2000, 8,80-88.

Nomenclature of the human immunoglobulin kappa (IGK) genes (Review) Lefranc M.-P. Exp Clin Immunogenet. 2001; 18: 161-174. Medline 11549845

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc 2003 Citation This paper should be referenced as such : Lefranc MP . IGK (Immunoglobulin Kappa). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IgKID17.html Lefranc MP . IGK (Immunoglobulin Kappa). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IgKID17.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -513- Atlas of Genetics and Cytogenetics in Oncology and Haematology

IGL (Immunoglobulin Lambda)

Identity Note The human IGL locus is located on chromosome 22 on the long arm, at band 22q11.2 The orientation of the locus has been determined by the analysis of translocations, involving the IGL locus, in leukemia and lymphoma. Sequencing of the long arm of chromosome 22 showed that it encompasses about 35 megabases of DNA and that the IGL locus is localized at 6 megabases from the centromere. Although the correlation between DNA sequences and chromosomal bands has not yet been made, the localization of the IGL locus can be refined to 22q11.2 Hugo IGL@ Location 22q11.2

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -514-

IGL V-GENE: Green box: Functional; Yellow box: Open reading frame; Red: Pseudogene. J-GENE: Grey: Functional . C-GENE: Blue: Functional; Blue open box: Pseudogene; Blue triangle: Not sequenced. GENES NOT RELATED: Purple open box: Pseudogene. for complete Figure, see: locus IGL, IMGT (The International ImMunoGeneTics information system ®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human IGL locus at 22q11.2 spans 1050 kb. It consists of 70 to 71 IGLV genes, localized on 900 kb, 7 to 11 IGLJ and 7 to 11 IGLC genes depending on the haplotypes, each IGLC gene being preceded by one IGLJ segment. Fifty-six to 57 genes belong to 11 subgroups, whereas 14 pseudogenes which are too divergent to be assigned to subgroups, have been assigned to 3 clans. The most 5' IGLV genes occupy the more centromeric position, whereas the IGLC genes, in 3' of the locus, are the most telomeric genes in the IGL locus. The potential genomic IGL repertoire comprises 29 to 32 functional IGLV genes belonging to 10 subgroups, 4 to 5 IGLJ, and 4 to 5 IGLC functional genes in the 7-IGLC gene haplotype. One, 2, 3 or 4 additional IGLC genes, each one probably preceded by one IGLJ, have been shown to characterize IGLC haplotypes with 8, 9, 10 or 11 genes, but these genes have not yet been sequenced. Two IGLV orphons have been identified on chromosome 8 at 8q11.2 and one of them belonging to subgroup 8 has been sequenced. The recent sequencing of the chromosome 22q showed that the IGL locus is localized at 6 megabases from the centromere. Two IGLC orphons and two IGLV orphons have also been characterized on 22q outside of the major IGL locus (See also IMGT Repertoire) The total number of human IGL genes per haploid genome is 84-93 (90-99 genes, if the orphons are included) of which 37-42 genes are functional

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -515- List of the human IGL genes Protein

Description Proteins encoded by the IGL locus are the immunoglobulin lambda chains. They result from the recombination (or rearrangement), at the DNA level, of two genes: IGLV and IGLJ, with deletion of the intermediary DNA to create a rearranged IGLV-J gene. The rearranged IGLV-J gene is transcribed with one of the IGLC genes and translated into an immunoglobulin lambda chain. Translation of the variable germline genes involved in the IGLV-J rearrangements are available at IMGT Repertoire Protein displays. Compared to the germline genes, the rearranged variable genes will acquire somatic mutations during the B cell differentiation in the lymph nodes, which will considerably increase their diversity. These somatic mutations can be analysed using the IMGT/V-QUEST tool available at http://imgt.cines.fr Mutations Note Mutations which correspond to allelic polymorphisms of the functional germline IGLV, IGLJ and IGLC genes are described in the IMGT database: (IMGT Repertoire>Alignments of alleles) Implicated in Entity Translocations which frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements. IGLV or IGLJ recombination signals or isolated heptamer are observed at the breakpoints.

c-Immunoglobulin gene IgL at 22q11, in normal cells: PAC 1019H10 and PAC 869I1 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -516- Entity t(3;22)(q27;q11); involve BCL6 in 3q27 Disease B-cell non-Hodgkin lymphomas (NHL), mainly diffuse large cell lymphoma; adult aggressive lymphoma Prognosis controversial

Entity t(8;22)(q24;q11); involve C-MYC in 8q24 Disease B-cell acute lymphoblastic leukemia (ALL3) and non-Hodgkin lymphomas (NHL), especially in the Burkitt lymphoma (link) Prognosis the prognosis has evolved with new treatments

Breakpoints

External links Nomenclature Hugo IGL@ Cards Genomic and cartography Gene and transcription Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases General knowledge Other databases Other IGL@ - IMGT database Probes Probe Probes IMGT Probe Immunoglobulin gene IgL at 22q11, in normal cells (Bari)

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -517- Probe IGL@ Related clones (RZPD - Berlin) PubMed Bibliography Emanuel BS, Cannizzaro LA, Magrath I, Tsujimoto Y, Nowell PC, Croce CM. Chromosomal orientation of the lambda light chain locus: V lambda is proximal to C lambda in 22q11. Nucleic Acids Res. 1985 Jan 25;13(2):381-7. Medline 3923432

Organization of the human immunoglobulin lambda light-chain locus on chromosome 22q11.2. Frippiat JP, Williams SC, Tomlinson IM, Cook GP, Cherif D, Le Paslier D, Collins JE, Dunham I, Winter G, Lefranc MP. Hum Mol Genet. 1995 Jun;4(6):983-91. Medline 7655473

The organization of the human immunoglobulin lambda gene locus. Kawasaki K, Minoshima S, Schooler K, Kudoh J, Asakawa S, de Jong PJ, Shimizu N. Genome Res. 1995 Sep;5(2):125-35. Medline 9132267

One-megabase sequence analysis of the human immunoglobulin lambda gene locus. Kawasaki K, Minoshima S, Nakato E, Shibuya K, Shintani A, Schmeits JL, Wang J, Shimizu N. Genome Res. 1997 Mar;7(3):250-61. Medline 9074928

Protein displays of the human immunoglobulin heavy, kappa and lambda variable and joining regions. Scaviner D, Barbie V, Ruiz M, Lefranc MP. Exp Clin Immunogenet. 1999;16(4):234-40. Medline 10575277

Human immunoglobulin C lambda 6 gene encodes the Kern+Oz-lambda chain and C lambda 4 and C lambda 5 are pseudogenes. Dariavach P, Lefranc G, Lefranc MP. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9074-8. Medline 3122211

Structure and expression of the human immunoglobulin lambda genes. Vasicek TJ, Leder P. J Exp Med. 1990 Aug 1;172(2):609-20. Medline 2115572

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -518- Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia. Ghanem N, Dariavach P, Bensmana M, Chibani J, Lefranc G, Lefranc MP. Exp Clin Immunogenet. 1988;5(4):186-95. Medline 2908491

Allelic polymorphisms and RFLP in the human immunoglobulin lambda light chain locus. Lefranc MP, Pallares N, Frippiat JP. Hum Genet. 1999 May;104(5):361-9. Medline 10394926

Nomenclature of the human immunoglobulin genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1P.1-A.1P.37.

The Immunologist FactsBook (Review) Lefranc M-P. and Lefranc G. Academic Press, London, UK (458 pages), 2001, ISBN:012441351X

Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P. The immunologist, 2000, 8,80-88.

Nomenclature of the human immunoglobulin lambda (IGL) genes (Review) Lefranc M.-P. Exp Clin Immunogenet 2001; 18: 242-254. Medline 11872955

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc 2003

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -519- Citation This paper should be referenced as such : Lefranc MP . IGL (Immunoglobulin Lambda). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IgLID54.html Lefranc MP . IGL (Immunoglobulin Lambda). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IgLID54.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -520- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRA (T cell Receptor Alpha)

Identity Note The human TRA locus is located on the chromosome 14 on the long arm at band 14q11.2. The orientation of the locus has been determined by the analysis of translocations, involving the TRA and TRD loci, in leukemia and lymphoma. Hugo TRA@ Location 14q11.2

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -521-

TRA/TRD V-GENE: Green box: Functional; Red: Pseudogene. D-GENE: Blue: Functional. J-GENE: Yellow: Functional; Pale yellow: Open reading frame; Red: pseudogene. C-GENE: Blue: Functional. for complete Figure, see: locus TRA, IMGT (The International ImMunoGeneTics information system ®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human TRA locus at 14q11.2 spans 1000 kilobases (kb). It consists of 54 TRAV genes belonging to 41 subgroups, 61 TRAJ segments localized on 71 kb, and a unique TRAC gene. The most 5' TRAV genes occupy the most centromeric position, whereas the TRAC genes, 3' of the locus, is the most telomeric gene in the TRA locus. The organization of the TRAJ segments on a large area is quite unusual and has not been observed in the other immunoglobulin or T cell receptor loci. Moreover the TRD locus is nestled in the TRA locus between the TRAV and TRAJ segments. V-J-rearrangements in the TRA locus therefore result in deletion of the TRD genes localized on the same chromosome. That deletion occurs in two steps, that is a deletion of the TRD genes, involving specific sequences located upstream from TRDC (sequence pseudo J alpha) would take place before the TRAV-J rearrangement. The potentiel genomic TRA repertoire comprises 45-47 functional

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -522- TRAV genes belonging to 33-35 subgroups, 50 functional TRAJ segments, and the unique TRAC gene. Among the variable genes are included five genes designated as TRAV/DV which belong to five different subgroups and which have been found rearranged either to TRAJ or to TRDD segments and can therefore be used in the synthesis of alpha or delta chains. The total number of human TRA genes per haploid genome is 116 of which 96 to 98 genes are functional. Enhancer sequences have been characterized 4.5kb 3' from TRAC. List of the human TRA genes Protein

Description Proteins encoded by the TRA locus are the T cell receptor alpha chains. They result from the recombination (or rearrangement), at the DNA level, of two genes: TRAV and TRAJ, with deletion of the intermediary DNA to create a rearranged TRAV-J gene. The rearranged TRAV-J gene is transcribed with the TRAC gene and translated into an T cell receptor alpha chain. Translation of the variable germline genes involved in the TRAV-J rearrangements are available at IMGT Repertoire Protein displays. TRA V-J rearrangements can be analysed using the IMGT/V-QUEST tool. Mutations Note Mutations which correspond to allelic polymorphisms of the functional germline TRAV, TRAJ and TRAC genes are described in the IMGT database: (IMGT Repertoire>Alignments of alleles) Implicated in Entity Translocations which frequently result from errors of the recombinase enzyme complex (RAG1, RAG2, etc.), which is responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements. TRAV or TRAJ recombination signals or isolated heptamer are observed at the breakpoints.

Entity t(1;14)(p32;q11); involve TAL1 in 1p32 Prognosis median survival > 5 yrs in children

Entity t(8;14)(q24;q11); involve MYC in 8q24 Disease T-cell acute lymphocytic leukemia (ALL); rare

Entity t(10;14)(q24;q11); involve HOX11 in 10q24 Disease T- cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) Prognosis not unfavourable

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -523- Entity t(11;14)(p13;q11); involve RBTN2 in 11p13 Disease T-cell acute lymphocytic leukemia (ALL)

Entity t(14;14)(q11;q32), inv(14)(q11q32); involve TCL1 in 14q32 Disease T-cell prolymphocytic leukemia (T-PLL) and adult T cell leukemia/lymphoma Prognosis poor

Entity t(14;21)(q11;q22); involve OLIG2 in 21q22 Disease T-cell acute lymphoblastic leukemia (ALL) Prognosis unknown

Breakpoints

External links Nomenclature Hugo TRA@ GDB TRA@ Entrez_Gene TRA@ 6955 T cell receptor alpha locus Cards Atlas TCRAID39 GeneCards TRA@ Ensembl TRA@ Genatlas TRA@ GeneLynx TRA@

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -524- eGenome TRA@ euGene 6955 Genomic and cartography GoldenPath TRA@ - 14q11.2 Ensembl TRA@ - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TRA@ Gene and transcription

Genbank BC020840 [ SRS ] BC020840 [ ENTREZ ]

Genbank BC022317 [ SRS ] BC022317 [ ENTREZ ]

Genbank BC063385 [ SRS ] BC063385 [ ENTREZ ]

Genbank BC063432 [ SRS ] BC063432 [ ENTREZ ]

Genbank BC070329 [ SRS ] BC070329 [ ENTREZ ] AceView TRA@ AceView - NCBI TRASER TRA@ Traser - Stanford

Unigene Hs.546375 [ SRS ] Hs.546375 [ NCBI ] HS546375 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P01848 [ SRS] P01848 [ EXPASY ] P01848 [ INTERPRO ] CluSTr P01848 Blocks P01848 Polymorphism : SNP, mutations, diseases OMIM 186880 [ map ] GENECLINICS 186880

SNP TRA@ [dbSNP-NCBI]

SNP TRA@ [GeneSNPs - Utah] TRA@ [SNP - CSHL] TRA@] [HGBASE - SRS] General knowledge Family TRA@ [UCSC Family Browser] Browser SMD Hs.546375 SAGE Hs.546375 Amigo function|MHC protein binding Amigo process|cellular defense response Amigo component|integral to membrane Amigo component|integral to plasma membrane Amigo function|peptide antigen binding Amigo function|receptor activity BIOCARTA Activation of Csk by cAMP-dependent Protein Kinase Inhibits

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -525- Signaling through the T Cell Receptor BIOCARTA IL12 and Stat4 Dependent Signaling Pathway in Th1 Development BIOCARTA CTL mediated immune response against target cells BIOCARTA The Co-Stimulatory Signal During T-cell Activation BIOCARTA IL 17 Signaling Pathway BIOCARTA Role of MEF2D in T-cell Apoptosis BIOCARTA HIV Induced T Cell Apoptosis BIOCARTA T Cell Receptor Signaling Pathway BIOCARTA Lck and Fyn tyrosine kinases in initiation of TCR Activation BIOCARTA T Cell Receptor and CD3 Complex BIOCARTA T Cytotoxic Cell Surface Molecules BIOCARTA T Helper Cell Surface Molecules BIOCARTA Role of Tob in T-cell activation PubGene TRA@ Other databases Other TRA@ - IMGT database Probes Probe Cancer Cytogenetics (Bari) Probe TRA@ Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography

Nomenclature of the human T cell Receptor genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1O.1-A.1O.23.

The T cell Receptor FactsBook (Review) Lefranc M-P. and Lefranc G. Academic Press, London, UK (398 pages), 2001, ISBN:0124413528

Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P. The immunologist, 2000, 8,72-79.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -526- BiblioGene - INIST Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc 2003 Citation This paper should be referenced as such : Lefranc MP . TRA (T cell Receptor Alpha). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRAID39.html Lefranc MP . TRA (T cell Receptor Alpha). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRAID39.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -527- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRB (T cell Receptor Beta)

Identity Note The human TRB locus is located on chromosome 7 on the long arm, at band 7q35. The orientation of the locus has been determined by the analysis of translocations, involving the TRB locus, in leukemia and lymphoma Hugo TRB@ Location 7q35

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -528- TRB V-GENE: Green box: Functional; Yellow box: Open reading frame; Red: Pseudogene. D-GENE: Blue: Functional. J-GENE: Grey: Functional . C-GENE: Blue: Functional. GENES NOT RELATED: Purple: Functional; Purple open box: Pseudogene. for complete Figure, see: locus TRB, IGMT (The international ImMunoGeneTics information system®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human TRB locus at 7q35 spans 620 kb. It consists of 64-67 TRBV genes belonging to 32 subgroups. Except for TRBV30, localized downstream of the TRBC2 gene, in inverted orientation of transcription, all the other TRBV genes are located upstream of a duplicated D-J-C-cluster, which comprises, for the first part one TRBD, six TRBJ, and the TRBC1 gene, and for the second part, one TRBD, eight TRBJ, and the TRBC2 gene. The most 5' TRBV genes occupy the most centromeric position, whereas the TRBV30 gene, 3' of the locus, is the most telomeric gene in the TRB locus. The potentiel repertoire consists of 39-46 functional TRBV genes belonging to 21-23 subgroups, the two TRBD, thirteen TRBJ (6 from the first cluster and 7 from the second cluster), and the two TRBC genes. Six TRBV orphons have been localized on chromosome 9 at 9p21. Enhancer sequences have been characterized 5.5kb 3' from TRBC2. List of the human TRB genes Protein

Description Proteins encoded by the TRB locus are the T cell receptor beta chains. They result from the recombination (or rearrangement), at the DNA level, of three genes: TRBV, TRBD and TRBJ, with deletion of the intermediary DNA to create a rearranged TRBV-D-J gene. The rearranged TRBV-D-J gene is transcribed with one of the two TRBC genes and translated into a T cell receptor beta chain. Translation of the variable germline genes involved in the TRBV-D-J rearrangements are available at IMGT Repertoire Protein displays. TRB V-D-J rearrangements can be analysed using the IMGT/V-QUEST tool. Mutations Note Mutations which correspond to allelic polymorphisms of the functional germline TRBV, TRBD, TRBJ and TRBC genes are described in the IMGT database: (IMGT Repertoire>Alignments of alleles) Implicated in Entity Translocations which frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements. TRBV, TRBD or TRBJ recombination signals or isolated heptamer are frequently observed at the breakpoints

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -529- Entity t(1;7)(p34;q35); involve LCK in 1p34 Disease T-cell acute lymphocytic leukemia (ALL)

Entity t(1;7)(p32;q35); involve TAL1 in 1p32 Disease T-cell acute lymphocytic leukemia (ALL) Prognosis median survival > 5 yrs in children

Entity t(7;9)(q35;q32); involve TAL2 in 9q32 Disease T-cell acute lymphocytic leukemia (ALL)

Entity t(7;9)(q35;q34); involve TAN1 in 9q34 Disease T-cell acute lymphocytic leukemia (ALL)

Entity t(7;10)(q35;q24); involve HOX11 in 10q24 Disease T- cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) Prognosis not unfavourable

Entity t(7;11)(q35;p13); involve RBTN2 in 11p13 Disease T-cell acute lymphocytic leukemia (ALL)

Entity t(7;14)(q35;q32); involve TCL1 in 14q32 Disease T-cell lymphoproliferations

Entity t(7;19)(q35;p13); involve LYL1 in 19p13 Disease T-cell acute lymphoblastic leukemia (ALL)

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -530-

External links Nomenclature Hugo TRB@ GDB TRB@ Entrez_Gene TRB@ 6957 T cell receptor beta locus Cards Atlas TCRBID24 GeneCards TRB@ Ensembl TRB@ Genatlas TRB@ GeneLynx TRB@ eGenome TRB@ euGene 6957 Genomic and cartography GoldenPath TRB@ - 7q35 Ensembl TRB@ - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TRB@ Gene and transcription

Genbank U66059 [ SRS ] U66059 [ ENTREZ ]

Genbank U66060 [ SRS ] U66060 [ ENTREZ ]

Genbank U66061 [ SRS ] U66061 [ ENTREZ ] AceView TRB@ AceView - NCBI TRASER TRB@ Traser - Stanford Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -531- SwissProt P04435 [ SRS] P04435 [ EXPASY ] P04435 [ INTERPRO ]

Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ]

Interpro IPR003599 Ig [ SRS ] IPR003599 Ig [ EBI ]

Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ] CluSTr P04435

Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ]

Smart SM00409 IG [EMBL] Blocks P04435 Polymorphism : SNP, mutations, diseases OMIM 186930 [ map ] GENECLINICS 186930

SNP TRB@ [dbSNP-NCBI]

SNP TRB@ [GeneSNPs - Utah] TRB@ [SNP - CSHL] TRB@] [HGBASE - SRS] General knowledge Family TRB@ [UCSC Family Browser] Browser Amigo function|MHC protein binding Amigo process|immune response Amigo function|peptide antigen binding Amigo component|plasma membrane Amigo function|receptor activity PubGene TRB@ Other databases Other TRB@ - IMGT database Probes Probe TRB@ Related clones (RZPD - Berlin) PubMed PubMed 20 Pubmed reference(s) in LocusLink Bibliography

Nomenclature of the human T cell Receptor genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1O.1-A.1O.23.

The T cell Receptor FactsBook (Review) Lefranc M-P. and Lefranc G. Academic Press, London, UK (398 pages), 2001, ISBN:0124413528

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -532- Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P. The immunologist, 2000, 8,72-79.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc 2003 Citation This paper should be referenced as such : Lefranc MP . TRB (T cell Receptor Beta). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRBID24.html Lefranc MP . TRB (T cell Receptor Beta). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRBID24.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -533- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRD (T cell Receptor Delta)

Identity Note The TRD locus is embedded in the TRA locus, between the TRAV and TRAJ genes. The orientation of the locus has been determined by the analysis of translocations, involving the TRD locus, in leukemia and lymphoma Hugo TRD@ Location 14q11.2

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -534-

TRA/TRD V-GENE: Green box: Functional; Red: Pseudogene. D-GENE: Blue: Functional. J-GENE: Yellow: Functional; Pale yellow: Open reading frame; Red: Pseudogene. C-GENE: Blue: Functional. for complete Figure, see: locus TRD, IMGT (The International ImMunoGeneTics information system ®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human TRD locus at 14q11.2 comprises a cluster of one TRDV gene (TRDV2), three TRDD segments, and four TRDJ segments, upstream of the unique TRDC gene; another TRDV gene (TRDV3) is localized downstream of the TRDC gene, in inverted orientation of transcription. This cluster spans 60 kb and is localized inside the TRA locus, between the TRAV genes and the TRAJ segments. One TRDV gene (TRDV1) is localized at 360 kb upstream of the TRDC gene, among the TRAV genes. Five variable genes have been found rearranged to both (D)J segments of the TRD locus and TRAJ segments, and can therefore be used for the synthesis of both delta and alpha chains. These genes are described as TRAV/DV. The TRDV genes are unique members of different subgroups. All the TRD genes are functional, with the exception of one TRAV/DV, which has been found either functional or as a pseudogene. Enhancer sequences have been described between the TRDJ3 and the TRDC gene.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -535- List of the human TRD genes Protein

Description Proteins encoded by the TRD locus are the T cell receptor delta chains. They result from the recombination (or rearrangement), at the DNA level, of three genes: TRDV, TRDD and TRDJ, with deletion of the intermediary DNA to create a rearranged TRDV-D-J gene. The rearranged TRDV-D-J gene is transcribed with the TRDC gene and translated into a T cell receptor delta chain. Translation of the variable germline genes involved in the TRDV-D-J rearrangements are available at IMGT Repertoire Protein displays. TRD V-D-J rearrangements can be analysed using the IMGT/V-QUEST tool. Mutations Note Mutations which correspond to allelic polymorphisms of the functional germline TRDV, TRDD, TRDJ and TRDC genes are described in the IMGT database: (IMGT Repertoire>Alignments of alleles) Implicated in Entity Translocations which frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements. TRDV, TRDD or TRDJ recombination signals or isolated heptamer are frequently observed at the breakpoints.

Entity t(1;14)(p32;q11); involve TAL1 in 1p32 Prognosis median survival > 5 yrs in children

Entity t(8;14)(q24;q11); involve MYC in 8q24 Disease T-cell acute lymphocytic leukemia (ALL); rare

Entity t(10;14)(q24;q11); involve HOX11 in 10q24 Disease T- cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) Prognosis not unfavourable

Entity t(11;14)(p13;q11); involve RBTN2 in 11p13 Disease T-cell acute lymphocytic leukemia (ALL)

Entity t(11;14)(p15;q11); involve RBTN1 in 11p15 Disease T-cell Acute lymphocytic leukemia (ALL)

Entity t(14;14)(q11;q32), inv(14)(q11q32); involve TCL1 in 14q32

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -536- Disease T-cell prolymphocytic leukemia (T-PLL) and adult T cell leukemia/lymphoma Prognosis poor

Breakpoints

External links Nomenclature Hugo TRD@ GDB TRD@ Entrez_Gene TRD@ 6964 T cell receptor delta locus Cards Atlas TCRDID279 GeneCards TRD@ Ensembl TRD@ Genatlas TRD@ GeneLynx TRD@ eGenome TRD@ euGene 6964 Genomic and cartography GoldenPath TRD@ - 14q11.2 Ensembl TRD@ - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TRD@

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -537- Gene and transcription

Genbank M21624 [ SRS ] M21624 [ ENTREZ ]

Genbank X06557 [ SRS ] X06557 [ ENTREZ ] AceView TRD@ AceView - NCBI TRASER TRD@ Traser - Stanford

Unigene Hs.512047 [ SRS ] Hs.512047 [ NCBI ] HS512047 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 186810 [ map ] GENECLINICS 186810

SNP TRD@ [dbSNP-NCBI]

SNP TRD@ [GeneSNPs - Utah] TRD@ [SNP - CSHL] TRD@] [HGBASE - SRS] General knowledge Family TRD@ [UCSC Family Browser] Browser SMD Hs.512047 SAGE Hs.512047 PubGene TRD@ Other databases Other TRD@ - IMGT database Probes Probe Probes IMGT Probe TRD@ Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography

Nomenclature of the human T cell Receptor genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1O.1-A.1O.23.

The T cell Receptor FactsBook (Review) Lefranc M-P. and Lefranc G. Academic Press, London, UK (398 pages), 2001, ISBN:0124413528

Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -538- The immunologist, 2000, 8,72-79.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc 2003 Citation This paper should be referenced as such : Lefranc MP . TRD (T cell Receptor Delta). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRDID279.html Lefranc MP . TRD (T cell Receptor Delta). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRDID279.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -539- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRG (T cell Receptor Gamma)

Identity Note The human TRG locus is located on chromosome 7, at band 7p15-p14 The orientation of the locus has been determined by the analysis of chromosome 7 inversions inv(7)(p15-q35), involving the TRG and TRB loci in ataxia telangiectasia patients, and in leukaemia. Hugo TRG@ Location 7p15-p14

DNA/RNA

TRG V-GENE: Green box: Functional; Yellow box: Open reading frame; Red: Pseudogene; Triangle: Not sequenced. J-GENE: Grey: Functional . C-GENE: Blue: Functional. for complete Figure, see: locus TRG, IMGT (The International ImMunoGeneTics information system ®) © Copyright 1995-2003 IMGT, IMGT is a CNRS trademark

Description The human TRG locus at 7p15-p14 spans 160 kb. It consists of 12- 15 TRGV genes belonging to 6 subgroups, upstream of a duplicated J- C-cluster, which comprises, for the first part, three TRGJ and the TRGC1 gene, and for the second part, two TRGJ and the TRGC2 gene.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -540- The most 5' TRGV genes occupy the most centromeric position, whereas the TRGC2 gene, 3' of the locus, is the most telomeric in the TRG locus. The potentiel repertoire consists of 4-6 functional TRGV genes belonging to two subgroups, the 5 TRGJ and the 2 TRGC genes. Polymorphisms in the number of TRGV genes and in the exon number of the TRGC2 gene have been described in different populations. Enhancer and silencer sequences have been characterized downstream of the TRGC2 gene List of the human TRG genes Protein

Description Proteins encoded by the TRG locus are the T cell receptor gamma chains. They result from the recombination (or rearrangement), at the DNA level, of two genes: TRGV and TRGJ, with deletion of the intermediary DNA to create a rearranged TRGV-J gene. The rearranged TRGV-J gene is transcribed with one of the two TRGC genes and translated into an T cell receptor gamma chain Translation of the variable germline genes involved in the TRGV-J rearrangements are available at IMGT Repertoire Protein displays. TRG V-J rearrangements can be analysed using the IMGT/V-QUEST tool. Mutations Note Mutations which correspond to allelic polymorphisms of the functional germline TRGV, TRGJ and TRGC genes are described in the IMGT database: (IMGT Repertoire>Alignments of alleles) Implicated in Entity Inversions which result from errors of the recombinase enzyme complexe (RAG1, RAG2, etc.), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements. TRGV or TRGJ recombination signals or isolated heptamer are observed at the breakpoints

External links Nomenclature Hugo TRG@ GDB TRG@ Entrez_Gene TRG@ 6965 T cell receptor gamma locus Cards Atlas TCRGID268 GeneCards TRG@ Ensembl TRG@ Genatlas TRG@

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -541- GeneLynx TRG@ eGenome TRG@ euGene 6965 Genomic and cartography GoldenPath TRG@ - Ensembl TRG@ - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TRG@ Gene and transcription

Genbank AC006033 [ SRS ] AC006033 [ ENTREZ ]

Genbank AC007245 [ SRS ] AC007245 [ ENTREZ ] AceView TRG@ AceView - NCBI TRASER TRG@ Traser - Stanford Protein : pattern, domain, 3D structure

SwissProt P03986 [ SRS] P03986 [ EXPASY ] P03986 [ INTERPRO ] CluSTr P03986 Blocks P03986 Polymorphism : SNP, mutations, diseases OMIM 186970 [ map ] GENECLINICS 186970

SNP TRG@ [dbSNP-NCBI]

SNP TRG@ [GeneSNPs - Utah] TRG@ [SNP - CSHL] TRG@] [HGBASE - SRS] General knowledge Family TRG@ [UCSC Family Browser] Browser Amigo process|immune response Amigo component|integral to plasma membrane Amigo function|transmembrane receptor activity PubGene TRG@ Other databases Other - IMGT database Probes Probe TRG@ Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -542-

Nomenclature of the human T cell Receptor genes (Review) Lefranc M-P. Current Protocols in Immunology 2000, Wiley, J. and Sons, New York, Supplement 40, A.1O.1-A.1O.23.

The T cell Receptor FactsBook (Review) Lefranc M-P. and Lefranc G. Academic Press, London, UK (398 pages), 2001, ISBN:0124413528

Locus Map and Genomic repertoire of the Human Immunoglobulin Genes (Review) Lefranc M-P. The immunologist, 2000, 8,72-79.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Marie-Paule Lefranc 2000 Updated 09- Marie-Paule Lefranc 2003 Citation This paper should be referenced as such : Lefranc MP . TRG (T cell Receptor Gamma). Atlas Genet Cytogenet Oncol Haematol. July 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRGID268.html Lefranc MP . TRG (T cell Receptor Gamma). Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCRGID268.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -543- Atlas of Genetics and Cytogenetics in Oncology and Haematology

11q23 rearrangements in leukaemia

Clinics and Pathology Disease de novo and therapy related leukaemias; acute non lymphocytic leukaemia (ANLL) and acute lymphocytic leukaemia (ALL) grossly represent half cases each; myelodysplasia (MDS) in the remaining 5%; biphenotypic leukaemia at times (likely to be more frequent with more investigations); 11q23 rearrangements in treatment related leukaemias (5-10% of 11q23 cases) are found mainly following a treatment with anti-topoisomerase II, or an intercalating topoisomerase II inhibitor, but also after alkylating agents treatment and/or radiotherapy; the prior cancer is variable. Phenotype / ANLL: M5a in half cases, M4 (20%), M1 or M5b (10% each), M2 (5%); cell stem ALL: B-cell mostly, L1 or L2, CD19+ in 60% of B-ALL cases, CD10+ origin 35%; T-ALL in rare cases (<1%); MDS: most often RA or RAEB1T. Epidemiology 25% are infant (<1 yr) cases; children and adults each represent 50% of cases; M/F = 0.9 (NS) See also 11q23 rearrangements in childhood acute lymphoblastic leukemia: Clinical aspects and congenital leukemias Clinics organomegaly; frequent CNS involvement (5%); high WBC (> 50 X 109/l in 40%).

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -544-

Molecular studies have identified a human homologue of the drosophila trithorax gene (designed HRX or MLL). MLL is a developmental regulator and is structurally altered in leukemia associated translocations that show an abnormality at band 11q23. The MLL gene on 11q23 is involved in a number of translocations with different partner chromosomes. The most common translocations observed in childhood AML are the t(9;11)(p21;q23) and the t(11;19)(q23;p13.1); other translocations of 11q23 involve at least 30 different partners chromosomes. Molecular studies have shown that MLL is rearranged more frequently than is revealed by conventional cytogenetic studies. A partial tandem duplication of MLL gene has also been reported in the majority of adult patients whose leukemic blast cells have a +11 and in some with normal karyotype. There is a strong association between AML M5/M4 and deletion and translocations involving 11q23. Sometimes cases of 11q23 M5B and M4, and occasionally M2 or M1 also show MLL rearrangement. Two clinical subgroups of patients have a high frequency of 11q23 aberration and M5 subtypes: one is AML in infants with MLL rearrangement in about 50% of cases; the other group is "secondary leukemia" (sAML) potentially after treatment with DNA topoisomerase II inhibitors. In general the translocations in these leukemia are the same as those occurring in "de novo" leukemia i.e. t(9;11), t(11;19) - Courtesy Georges Flandrin, CD-ROM AML/MDS G. Flandrin/ICG. TRIBVN

Prognosis very poor in general; variable according to the translocation, the phenotype, the age , and whether the leukaemia is de novo or treatment related. Cytogenetics Cytogenetics I- the most frequent are: Morphological normal karyotype: a partial tandem duplication (in situ) of MLL is present in a percentage of ANLL with a normal karyotype; LARG, in 11q23, has been found fused to MLL +11 : 1% of ANLL and MDS as well; M1, M2, and M4 ANLL;

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -545- therapy related ANLL; MDS evolving towards ANLL; partial tandem duplication (in situ) of MLL; visible dup(11q) also occur. t(4;11)(q21;q23) : represent 1/3 of cases; found mainly (95%) in B- ALL (CD19+ in 75%, CD10+ in 15%); treatment related ALL in 5%; unbalanced sex ratio < 4 yrs (1M/2F); children represent half cases (infants (<1 yr) accounting for 1/3 of all cases); children aged 2-9 yrs appear to have a much better prognosis; the gene involved in 4q21 is AF4, a transcription activator. t(6;11)(q27;q23) : 5% of cases; mostly; children and young adults; male predominance; the gene involved in 6q27 is AF6; role in signal transduction. t(9;11)((p23;q23) : represent 1/4 of cases; found in ANLL mainly in M5a (70%), or M4 (10%); in ALL in 10%; de novo and therapy related AL; children represent half cases (infants (<1 yr) accounting for 15% of all cases); the gene involved in 9p22 is AF9, a transcription activator. t(10;11)(p12;q23) : 5% of cases; M4 or M5 ANLL; ALL at times; from infants and children to (rare) adult cases; the gene involved in 10p12 is AF10, a transcription activator. t(11;19)(q23;p13.1) : 5% of cases; M4 or M5 ANLL most often; de novo and therapy related AL; adults mainly; the gene involved in 19p13.1 is ELL, a transcription activator. t(11;19)(q23;p13.3) : 5% of cases; ALL, biphenotypic AL and ANLL (M4/M5 mainly); therapy related AL; T-cell ALL at times, these T-cell cases are the only cases of t(11;19) with an excellent prognosis, a rather rare feature in this page!!; mostly found in infants (half cases), and other children (altogether: 70%), or young adults (cases > 40 yrs are 4%; 23 unpublished cases and a review of 90 cases); the gene involved in 19p13.3 is ENL, a transcription activator. II- Various other11q23 rearrangements have be described; these are rare, some are even poorly known, but the ones listed below are recurrent and/or with ascertainement of a partner gene to MLL: inv(11)(p15q23) : ANLL and MDS. del(11q): one case (t-ANLL) showed involvement of GAS7, a gene sitting in 17p13; del(11q) with MLL rearrangement is likely to be heterogeneous, as MLL shows multiple possible partners, and, not rarely, complex translocations. t(X;11)(q13;q23) : ANLL; the gene involved in Xq13 is AFX1, a transcription regulator. t(X;11)(q22;q23); the gene in Xq22 is Septin2 t(1;11)(p32;q23) : ALL and ANLL; the gene involved in 1p32 is AF1P. t(1;11)(q21;q23) : mostly M4 ANLL; the gene involved in 1q21 is AF1q. t(2;11)(p21;q23) : ANLL and MDS; may be found associated with del(5q) t(2;11)(q11;q23) the gene in 2q11 is LAF4 t(3;11)(p21;q23) : the gene involved in 3p21 is AF3p21 t(3;11)(q25;q23); the gene in 3q25 is GMPS t(5;11)(q31;q23), and ins(5;11)(q31;q13q23); the latter involve

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -546- AF5q31 in 5q31; very rare t(5;11)(q31;q23) the gene in 5q31 is GRAF t(6;11)(q21;q23): ANLL; the gene in 6q21 is AF6q21, a transcription regulator t(9;11)(q34;q23) the gene in 9q34 is AF9q34 t(10;11)(p11.2;q23); the gene in 10p11.2 is ABI1 t(10;11)(q22;q23) t(11;11)(q13;q23) t(11;12)(q23;q13) t(11;14)(q23;q24) the gene in 14q24 is h-gephyrin t(11;15)(q23;q14) the gene in 15q14 is AF15q14 t(11;15)(q23;q15) t(11;16)(q23;p13) : treatment related ANLL/MDS; most cases are children cases; the gene involved in 16p13 is CBP, a transcriptional adaptor/coactivator t(11;17)(q23;p13); the gene in 17p13 is GAS7 t(11;17)(q23;q12); the gene in 17q12 is RARa t(11;17)(q23;q21) : ANLL; the gene involved in 17q21 is AF17; not to be confused with the in M3 ANLL variant, with involvement of PLZF in 11q23 and RARa in 17q21 t(11;17)(q23;q25): ANLL and MDS; the gene in 17q25 is MSF/AF17q25 t(11;18)(q23;q23) t(11;19)(q23;p13) : ANLL ; the gene in 19p13 is EEN t(11;21)(q23;q11) t(11;22)(q23;q13) : ANLL; the gene in 22q13 is P300 t(11;22)(q23;q11.2) : ANLL; the gene in 22q11.2 is hCDCRel III- Finally, various other breakpoints with 11q23 have been described, but without gene ascertainment: Xq24, 1q32, 2q37, 7q22, 7q32, 8q11, 9p11, 9q33, 12p13, 12q24, 14q11, 14q32, 17q11, 18q12, 20q13, ... Additional +X and i(7q) in the t(4;11); +8, +19, +21 in the t(6;11); +8 and +19 in anomalies the t(9;11); inv(11) in the t(10;11); +X, +6 and +8 in the 19p13.3; +8 in the 19p13.1 Genes involved and Proteins Gene MLL Name Location 11q23 21 exons, spanning over 100 kb; 13-15 kb mRNA; coding sequence: Dna / Rna 11.9 kb. Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation; wide expression; homology with trithorax (drosophila). Gene variable gene, from a variable chromosome partner (see above) Name

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -547- these genes appear to have, in most cases, no apparent homology to Dna / Rna each other; for DNA and protein description of each, refer to their gene entry. Result of the chromosomal anomaly Hybrid gene

MLL and partners - Editor, 06/2000, last update 09/2001. We implore researchers not to discover further MLL partners: there is no more room.

Description 5' MLL- 3' partner; highly variable breakpoints on the partner

Fusion N-term AT hook and DNA methyltransferase from MLL fused to (little or Protein most of) the partner C-term part; the reciprocal ( partner-MLL) may or Description may not be expressed.

To be noted cases with MLL involvement in rare translocations are yet poorly known; additional cases are needed to delineate the entities; we propose that detailed cases reports are herein collected and published; if you have a

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -548- case with iconography, please, contact us Bibliography Acute leukemia with chromosome translocation (4;11): 7 new patients and analysis of 71 cases. Lampert F, Harbott J, Ludwig WD, Bartram CR, Ritter J, Gerein V, Neidhardt M, Mertens R, Graf N, Riehm H Blut. 1987 Jun;54(6):325-35. Medline 3496135

Characteristics of trisomy 11 in childhood acute leukemia with review of the literature. Ingram L, Raimondi SC, Mirro J Jr, Rivera GK, Ragsdale ST, Behm F Leukemia. 1989 Oct;3(10):695-8. Review. Medline 2674563

Implication of prior treatment with drug combinations including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation. Albain KS, Le Beau MM, Ullirsch R, Schumacher H Genes Chromosomes Cancer. 1990 May;2(1):53-8. Review. Medline 2177642

Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases Pui CH, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ, Head DR, Crist WM, Land VJ, Pullen DJ, Steuber CP, et al Blood. 1991 Feb 1;77(3):440-7. Medline 1991161

Cytogenetic heterogeneity in t(11;19) acute leukemia: clinical, hematological and cytogenetic analyses of 48 patients--updated published cases and 16 new observations. Huret JL, Brizard A, Slater R, Charrin C, Bertheas MF, Guilhot F, Hahlen K, Kroes W, van Leeuwen E, Schoot EV, et al Leukemia. 1993 Feb;7(2):152-60. Review. Medline 8426468

Childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): an update. Pui CH, Carroll LAJ, Raimondi SC, Shuster JJ, Crist WM, Pullen DJ Blood. 1994 Apr 15;83(8):2384-5. No abstract available. Medline 8161808

Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations. Bernard OA, Berger R

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -549- Genes Chromosomes Cancer. 1995 Jun;13(2):75-85. Review. Medline 7542910

Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia. Schichman SA, Canaani E, Croce CM JAMA. 1995 Feb 15;273(7):571-6. Review Medline 7837391

11q23 rearrangements in acute leukemia. Rubnitz JE, Behm FG, Downing JR Leukemia. 1996 Jan;10(1):74-82. Review. Medline 8558942

Chromosome abnormalities in leukaemia: the 11q23 paradigm. Young BD, Saha V Cancer Surv. 1996;28:225-45. Review. Medline 8977038

Adenoviral E1A-Associated Protein p300 Is Involved in Acute Myeloid Leukemia With t(11; 22)(q23; q13). Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M , Ohki M, Hayashi Y. Blood 1997; 90: 4699-4704. Medline 98052522

All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Rowley JD, Reshmi S, Sobulo O, Musvee T, Anastasi J, Raimondi S, Schneider NR, Barredo JC, Cantu ES, Schlegelberger B, Behm F,Doggett NA, Borrow J, Zeleznik- Le N Blood. 1997 Jul 15;90(2):535-41. Medline 9226152

Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC Genomics. 1998 Jan 15;47(2):187-99. Medline 9479491

Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants. Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):811-22. Medline 9593286

Hematologic malignancies with t(4;11)(q21;q23)--a cytogenetic,morphologic,

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -550- immunophenotypic and clinical study of 183 cases.European 11q23 Workshop participants. Johansson B, Moorman AV, Haas OA, Watmore AE, Cheung KL, Swanton S, Secker-Walker LM Leukemia. 1998 May;12(5):779-87. Medline 9593281

Derivative chromosomes of 11q23-translocations in hematologic malignancies. European 11q23 Workshop participants. Johansson B, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):828-33. Medline 9593288

The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. European 11q23 Workshop participants Lillington DM, Young BD, Berger R, Martineau M, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):801-4. Medline 9593284

The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases. EU Concerted Action 11q23 Workshop participants. Martineau M, Berger R, Lillington DM, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):788-91. Medline 9593282 t(11;22)(q23;q11.2) in acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML, Felix CA. Proc Natl Acad Sci 1998; 95: 6413-6418.

The translocations, t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3): a cytogenetic and clinical profile of 53 patients. European 11q23 Workshop participants. Moorman AV, Hagemeijer A, Charrin C, Rieder H, Secker-Walker LM Leukemia. 1998 May;12(5):805-10. Medline 9593285

General Report on the European Union Concerted Action Workshop on 11q23, London, UK, May 1997.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -551- Secker-Walker LM Leukemia. 1998 May;12(5):776-8. Medline 9593280

Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop. Secker-Walker LM, Moorman AV, Bain BJ, Mehta AB Leukemia. 1998 May;12(5):840-4. Medline 9593290

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants. Swansbury GJ, Slater R, Bain BJ, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):792-800. Medline 9593283

ABI-1, a human homolog to mouse Abl-Interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). Taki T, Shibuya N, Taniwaki M, Hanada R, Morishita K, Bessho F, Yanagisawa M, Hayashi Y. Blood 1998; 92: 1125-1130.

MLL is involved in a t(2;11)(p21;q23) in a patientwith acute myeloblastic leukemia. Fleischman EW, Reshmi S, Frenkel MA, Konovalova VI, Guleva GP, Kulagina OE, Konstantinova LN, Tupitsyn NN, Rowley JD. Gene Chromosom Cancer 1999; 24: 151- 155. Medline 99101073 t(3;11)(q25;q23) fuses MLL with the GMPS (guanosine 5'-monophosphate synthetase) gene in treatment-related acute myeloid leukemia (AML). Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rappaport EF, Felix CA. Blood 1999; 94 Suppl 1: Abst 2227

Involvement of the MLL and RARA genes in a patient with acute monocytic leukemia with t(11;17)(q23;q12). Robert L. Redner, Susanne M. Gollin, Sandra S. Kaplan, Sofia Shekhter-Levin. Blood 1999; 94 Suppl 1: Abst 3978

AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. Proc Natl Acad Sci USA 1999; 96: 14535-14540.

The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -552- myeloid leukemia with a deletion 5q. Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U, Viehmann S, Henn T, Korth P, Scharr D, Lampert F. Proc Natl Acad Sci U S A. 2000; 97: 9168-9173. Medline 20381355

AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14). Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R. Oncogene 2000;19: 4446-4450. Medline 20438193

A human homologue of the rat gephyrin gene is fused to MLL in a de novo leukemia with t(11;14)(q23;q24). Kuwada N, Kimura F, Matsumura T, Yamashita T, Nakamura Y, Ikeda T, Sato K, Motoyoshi K. Blood 2000; 96 Suppl 1: Abst 4396.

Identification of septin 2 as a new partner gene of MLL in infant aml with a complex translocation. Slater DJ, Hilgenfeld E, Rappaport EF, Shah NR, Megonigal MD, Ried T, Felix CA. Blood 2000; 96 Suppl 1: Abst 2976.

Cloning of unknown MLL fusion transcripts identifies two novel MLL fusion partners. von Bergh A, Beverloo B, Slater R, Groot A, Rombout P, Kluin P, Schuuring E. Blood 2000; 96 Suppl 1: Abst 2984.

Contributor(s) Written 08- Jean-Loup Huret 1998 Updated 09- Jean-Loup Huret 1998 Updated 06- Jean-Loup Huret 2000 Updated 01- Jean-Loup Huret 2001 Updated 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -553- Haematol. August 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. September 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. June 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -554- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Anaplasic large cell lymphoma (ALCL)

Identity Note Anaplasic large cell lymphoma can be classified into : 1- primary systemic ALK+ ALCL 2- primary systemic ALK- ALCL 3- primary cutaneous ALCL. (see in paragraph Pathology) NOTE The 2 first categories are defined according to the involvement (or not) of ALK in fusion proteins with various partners (see below); ALK+ ALCL cases are sometimes called ALK lymphomas, or ALKomas ALK+ ALCL can be further divided into t(2;5) cases, with NPM1-ALK fusion protein which localises both in the cytoplasm and in the nucleus, and t(2;Var), involving various partners and ALK, and a cytoplasmic localization of the fusion protein; the latter are called "cytoplasm only" ALK+ ALCL. ALCL may also arise from transformation of another lymphoma mycosis fungoides, peripheral T-cell lymphoma, ...); these ALCL are called secondary ALCL, and they bear a poor prognosis Clinics and Pathology Epidemiology ALCL represent about 5% of non Hodgkin lymphomas (NHL) in adults, and 15 % of pediatric NHL (i.e. 20-30 % of large cell lymphomas in children). ALK+ ALCL represent 50 to 60 % of ALCL cases. ALK+ ALCL predominantly affect young male patients (most cases occur before the age of 40 yrs) , while ALK- ALCL is found in older patients (median age around 50 yrs) of both sex Clinics ALK+ ALCL presents as an aggressive disease with systemic signs, and extranodal sites (bone marrow, skin, bone, soft tissues, and organs); less agressive presentation in ALK- ALCL cases (but a worse prognosis, see below) Note: ALK+ ALCL without the t(2;5) (so called cytoplasmic only ALK cases) show clinical features similar to those of classical ALK+ ALCL. Were found in a recent series: mean age: 19 yrs, range 4 to 45 yrs; male/female ratio: 1.5, presentation with advanced disease (stage III- IV in 9 of 15 cases), systemic symptoms (11/15), and frequent involvement of extranodal sites. Pathology 3 main histopathological types are found; the common type, characterized by large lymphoid cells with horseshoe shaped nuclei with many nucleoli, and large cytoplasm; may be ALK + or - ALCL the small cell type, together with the above described cells, show small and medium sized cells; almost exclusively ALK+ cases

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -555- the lymphohistiocytic type also contains a number of reactive histiocytes, which, earlier, lead to the misdiagnosis of malignant histiocytosis; almost always ALK+ cases. All the 3 forms contain large cells, positive for CD30 (on the cell membrane and the golgi ); they are mostly epithelial membrane antigen (EMA) positive. most cases are T-cell cases (often cytotoxic T-cells), or may be null cases, the null cases often involving the T-cell; B-cell cases may belong to a different category; ALK+/IgA+ immunoblastic large B-cell lymphomas could exist. Aside are primary cutaneous anaplasic large cell lymphomas, a disease with indolent clinical course, negative for ALK, lacking the t(2;5) or variant translocations, close to the benign lymphomatoid papulosis NOTE: there are cases where the differential diagnosis between Hodgkin disease (HD) -where CD30 is also strongly expressed- and ALCL is difficult (cases previously called ALCL-HD like). Prognosis ALK+ ALCL have a favourable prognosis, whichever the ALK parner is: 70% to 80 % 5 yr survival, while ALK- ALCL cases have a much poorer prognosis (5 yr survival in only 30% -40 %). ALK+ cases without NPM1 involvement Genetics The genetic background in ALK- cases remains unknown. ALK+ cases are the result of the formation of a hybrid gene between ALK and either NPM1 (in 70-80% of the cases), or TPM3 (in 20% of the cases) or, rarely: MSN, ATIC, TFG, CLTC, ALO17, or MYH9 (these latter being"cytoplasm only" or cytoplasmic (TPM3, ATIC, TFG, CLTC, ALO17, MYH9) or membrane restricted (MSN) ALK+ ALCL). Cytogenetics Cytogenetics t(2;5)(p23;q35) in the classical form with NPM1 involvement on Morphological chromosome 5, t(X;2)(q11;p23), t(1;2)(q25;p23), inv(2)(p23q35), t(2;3)(p23;q21), t(2;17)(p23;q23), t(2;17)(p23;q25) or t(2;22)(p23;q11.2) can also be found. Genes involved and Proteins Note these translocations involve ALK in 2p23, and either MSN in Xq11, TPM3 in 1q25, ATIC in 1q35, TFG in 3q21, NPM1 in 5q35, CLTC in 17q23, ALO17 in 17q25, and MYH9 in 22q11.2. Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor Gene MSN Name

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -556- Location Xq11 Protein 576 amino acids, 68 kDa; cytoskeleton protein; binds to the plasma membrane and interacts with actin. Gene TPM3 Name Location 1q25 Protein 284 amino acids, 33 kDa; coilde coil structure; role in Calcium dependant actin-myosin interaction Gene ATIC Name Location 2q35 Protein 591 amino acids, 64 kDa; bifunctional purine biosythesis:9th and 10th step of the de novo purine synthesis Gene TFG (tropomyosin receptor kinase-fused gene) Name Location 3q21 Protein 406 amino acids, 44 kDa; widely expressed Somatic apart from the TFG-ALK herein described, TFG is also known to de mutations fused to NTRK1 in a subset of thyroid papillary carcinomas Gene NPM1 Name Location 5q35 Protein nuclear localisation; RNA binding nucleolar phosphoprotein involved in preribosomal assembly Gene CLTC Name Location 17q23 Protein 1675 amino acids, 191 kDa; Component of the vesicles matrix originated from the plasma membrane or the golgi Gene ALO17 Name Location 17q25 Protein 1599 amino acids Gene MYH9 Name Location 22q11 Protein 1960 amino acids; 227 kDa; binds actin; protein of the cytoskeleton Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -557- Hybrid gene 5' partner - 3' ALK Description

Fusion N-term amino acids from the partner gene fused to the 562 C-term Protein amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with Description the tyrosine kinase domain); homodimerization of the fusion protein.

To be noted ALK and some of the above ALK partners, or closely related genes, are found implicated both in anaplasic large cell lymphoma and in inflammatory myofibroblastic tumours; this is a new concept, that 2 different types of tumour may result from the same chromosomal/genes rearrangement. Bibliography CD30-positive large cell lymphomas ('Ki-1 lymphoma') are associated with a chromosomal translocation involving 5q35. Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL, Kristoffersson U, Magaud JP, Nezelof C, Tilly H, Vannier JP, et al. Br J Haematol. 1990; 74: 161-168. Medline 90198855

Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non- Hodgkin's lymphoma. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT. Science. 1994; 263: 1281-1284. Medline 94167588

Analysis of the t(2;5)(p23;q35) translocation by reverse transcription- polymerase chain reaction in CD30+ anaplastic large-cell lymphomas, in other non-Hodgkin's lymphomas of T-cell phenotype, and in Hodgkin's disease. Wellmann A, Otsuki T, Vogelbruch M, Clark HM, Jaffe ES, Raffeld M. Blood. 1995; 86: 2321-2328. Medline 95391991

Cytogenetics of lymphomas: a brief review of its theoretical and practical significance Donner LR. Cancer Genet Cytogenet 1997; 94: 20-26. Medline 97233051

Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma- associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Bischof D, Pulford K, Mason DY, Morris SW.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -558- Mol Cell Biol. 1997; 17: 2312-2325. Medline 97220023

The Cryptic inv(2)(p23q35) Defines a New Molecular Genetic Subtype of ALK- Positive Anaplastic Large-Cell Lymphoma. Wlodarska I, De Wolf-Peeters C, Falini B, Verhoef G, Morris SW, Hagemeijer A, Van den Berghe H. Blood 1998; 92: 2688-2695.

Lymphomas Expressing ALK Fusion Protein(s) Other Than NPM-ALK. Falini B, Pulford K, Pucciarini A, Carbone A, De Wolf-Peeters C, Cordell J, Fizzotti M, Santucci A, Pelicci PG, Pileri S, Campo E, Ott G, Delsol G, Mason DY.. Blood 1999; 94: 3509-3515.

A New Fusion Gene TPM3-ALK in Anaplastic Large Cell Lymphoma Created by a (1;2)(q25;p23) Translocation. Lamant L, Dastugue N, Pulford K, Delsol G, Mariam+ B. Blood 1999; 93: 3088-3095. t(1;2)(q21;p23) and t(2;3)(p23;q21); Two novel variant translocations of the t(2;5)(p23;q35) in anaplastic large cell lymphoma. Rosenwald A, Ott G, Pulford K, Katzenberger T, K-hl J, Kalla J, Ott MM, Mason DY, M-ller-Hermelink HK. Blood 1999; 94: 362-364.

TRK-Fused Gene (TFG) Is a New Partner of ALK in Anaplastic Large Cell Lymphoma Producing Two Structurally Different TFG-ALK Translocations.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -559- Hernandez L, Pinyol M, Hernandez S, Bea S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E. Blood 1999; 94: 3265-3268.

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG. Leukemia 2000; 14: 1533-1559.

Anaplastic large cell lymphomas, Primary systemic (T/Null cell type). Delsol G, Ralfkiaer E, Stein H, Wright D, Jaffe E.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -560- World Health Organization (WHO) Classification of Tumors. Pathology and Genetics of tumours of Haematopoietic and Lymphoid Tissues . 2001 pp 230-235.

Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Morris SW, Xue L, Ma Z, Kinney MC. Br J Haematol 2001; 113: 275-295. Medline 21275125

Contributor(s) Written 08- Jean-Loup Huret 2001 Updated 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . Anaplasic large cell lymphoma (ALCL). Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL :

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -561- http://www.infobiogen.fr/services/chromcancer/Anomalies/AnaplLargeCelLymphID2103.html Huret JL . Anaplasic large cell lymphoma (ALCL). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/AnaplLargeCelLymphID2103.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -562- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(1;7)(p34;q34)

Clinics and Pathology Disease Specifically associated with T-cell Acute Lymphoblastic Leukemia (T- ALL). This translocation is related to LCK dysregulation. Phenotype / cell stem T lineage. origin Epidemiology Rare : < 1% among T-ALL Cytogenetics Cytogenetics 1p34 is a partner of 7q34. The other partners of 7q34 are 1p32, 9q32, Morphological 9q34, 10q24, 11p13, 15q22, 19p13. 22q13 is a novel partner of 1p34 in a precursor T-lymphoblastic leukemia. Genes involved and Proteins Gene TCRB : T-cell receptor beta-chain gene. Name Location 7q35 The TRB locus at 7q35 spans 685 Kb. The locus contains 2 types of coding elements : TCR elements (64-67 variable genes TRBV, 2 Dna / Rna clusters of diversity, joining and constant segments) and 8 trypsinogen genes. A portion of the TCRB locus has been duplicated and translocated to the chromosome 9 at 9p21. Protein T cell receptor beta chains. Gene LCK (lymphocyte-specific tyrosine kinase gene) Name Location 1p34 The LCK gene encodes a lymphocyte-specific member of the Src family of protein kinases. Size and orientation strand are unknown. This gene is assigned to bands 1p34.3 by fluorescence in situ hybridation and its mapping relative to the reference marker pYNZ2 (D1S57). LCK is normally expressed from two distinct promoters. Dna / Rna A proximal promoter initiates transcripts designated as type I. A distal promoter, found approximately 30 kb further upstream, initiates transcripts designated as type II. Human thymocytes and all the leukemic T cell lines express both type I and type II LCK transcripts, albeit at different levels. Peripheral blood

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -563- mature T cell express mainly type II LCK transcripts. The two types of human LCK transcripts are distingued by their 5'- untranslated regions. However, the protein kinase encoded by both transcripts is the same. Protein The human lymphocyte specific protein tyrosine kinase is a 57869kDa protein (p56LCK) 508 amino acids, involved in T-cell and IL2-receptor signaling important for antigen-induced T-cell activation. Result of the chromosomal anomaly Hybrid The T-cell acute lymphoblastic leukemia cell line HSB-2 has the gene t(1;7)(p34;q34) translocation. The T-cell acute lymphoblastic leukemia Description cell line SUP-T12 has the same translocation. The breakpoint in the HSB-2 cell line at 1p34 occurs between the type I and type II promoters and thus separates the two LCK promoters and the type II promoter is translocated to the der(7) chromosome. The breakpoint in the SUP-T12 at 1p34 occurs 2kb upstream of the type II promoter, leaving an intact LCK gene on the der(1) chromosome. In HSB-2 the t(1;7) fuses the TCRB constant region and transcriptionnal enhancer with the type I transcription unit of LCK on the der(1) chromosome. (the type II promoter is translocated to the der(7) chromosome). Thus the TCRB enhancer upregulates the type I trancripts. An independent t(1;7) in SUP-T12 also resulted in the juxtaposition of LCK to TCRB. The p56LCK protein is elevated approximately 2-fold in comparaison with that in normal T-cell lines and total cellular tyrosine phosphorylation is elevated approximately 10-fold.

Fusion No fusion protein. Protein Note Oncogenesis The oncogenic p56LCK in T-cell-leukemia lines contains an amino acid substitution within the CD4/CD8 binding domain, two substitutions in the kinase domain and an insertion between the SH2 and kinase domains. These mutations of LCK and the overexpression of p56LCK protein may contribute to some human T-cell leukemias.

External links Other t(1;7)(p34;q34) Mitelman database (CGAP - NCBI) database Other t(1;7)(p34;q34) CancerChromosomes (NCBI) database Bibliography The LCK gene is involved in the t(1 ;7)(p34 ;q34) in the T-cell acute lymphoblastic leukemia derivated cell line, HSB-2. Burnett RC, David JC, Harden AM, Le Beau MM, Rowley JD, Diaz MO

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -564- Genes Chromosomes Cancer 1991; 3(6): 461-467. Medline 1663780

Karyotype and T-cell receptor expression in T-lineage acute lymphoblastic leukemia. Secker-Walker LM, Campana D, Hawkins JM, Sampson RE, Coustan-Smith E. Genes Chromosomes Cancer 1992; 4(1): 41-45. Medline 1377008

Molecular analysis of the T-cell acute lymphoblastic leukemia -associated t(1 ;7)(p34 ;q34) that fuses LCK and TCRB. Burnett RC, Thirman MJ, Rowley JD, Diaz MO. Blood 1994; 84(4): 1232-1236. Medline 8049439

Cytogenetic abnormalities in adult acute lymphoblastic leukemia : correlations with hematologic findings outcome. A collaborative Study of the Groupe Franáais de CytogÇnÇtique HÇmatologique. Blood 1996; 87(8) : 3135-3142. Medline 8605327

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm F, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT Cancer Cell 2002; 1(1): 75-87. Medline 12086890

Contributor(s) Written 08/2003 Jacques Boyer Citation This paper should be referenced as such : Boyer J . t(1;7)(p34;q34). Atlas Genet Cytogenet Oncol Haematol. . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0107p34q34ID1045.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -565- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;17)(p23;q25)

Clinics and Pathology Disease Anaplasic large cell lymphoma: translocations involving 2p23 are found in more than half cases of anaplasic large cell lymphoma (ALCL), a high grade non Hodgkin lymphoma (NHL). They involve ALK, and are therefore called ALK+ ALCL. The most frequent ALK+ ALCL being the the t(2;5)(p23;q35) with NPM1 -ALK fusion protein, which localises both in the cytoplasm and in the nucleus. The t(2;17)(p23;q25) has so far been described in only 1 case, and, like other t(2;Var) involving various partners and ALK, the fusion protein has a cytoplasmic localization; they are therefore called "cytoplasm only" ALK+ ALCL. Clinics ALK+ ALCL without the t(2;5) (so called cytoplasmic only ALK cases) show clinical features similar to those of classical ALK+ ALCL: young age, male predominance, presentation with advanced disease, systemic symptoms, frequent involvement of extranodal sites, and a good prognosis. The t(2;17) case was that of a 53 yrs old man. Genes involved and Proteins Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor Gene ALO17 (ALK lymphoma oligomerization partner on chromosome 17) Name Location 17q25 Result of the chromosomal anomaly Hybrid gene 5' ALO17 - 3' ALK Description

Fusion N term ALO17 fused to the 562 C-term amino acids from ALK (i.e. the

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -566- Protein entire cytoplasmic portion of ALK with the tyrosine kinase domain) Description

External links Other t(2;17)(p23;q25) Mitelman database (CGAP - NCBI) database Other t(2;17)(p23;q25) CancerChromosomes (NCBI) database Bibliography CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B. Blood 2000; 96: 3681-3695.

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG. Leukemia 2000; 14: 1533-1559.

Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Morris SW, Xue L, Ma Z, Kinney MC. Br J Haematol 2001; 113: 275-295. Medline 21275125

Contributor(s) Written 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(2;17)(p23;q25). Atlas Genet Cytogenet Oncol Haematol. August 2003 .

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -567- URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0217p23q25ID1289.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -568- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;17)(p23;q23)

Clinics and Pathology Disease Anaplasic large cell lymphoma: translocations involving 2p23 are found in more than half cases of anaplasic large cell lymphoma (ALCL), a high grade non Hodgkin lymphoma (NHL). They involve ALK, and are therefore called ALK+ ALCL. The most frequent ALK+ ALCL being the the t(2;5)(p23;q35) with NPM1 -ALK fusion protein, which localises both in the cytoplasm and in the nucleus. The t(2;17)(p23;q23) has so far been described in only 1 case, and, like other t(2;Var) involving various partners and ALK, the fusion protein has a cytoplasmic localization; they are therefore called "cytoplasm only" ALK+ ALCL. Clinics ALK+ ALCL without the t(2;5) (so called cytoplasmic only ALK cases) show clinical features similar to those of classical ALK+ ALCL: young age, male predominance, presentation with advanced disease, systemic symptoms, frequent involvement of extranodal sites, and a good prognosis. The t(2;17) case was that of a 14 yrs old girl. Genes involved and Proteins Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor Gene CLTC Name Location 17q23 Protein 1675 amino acids, 191 kDa; component of the vesicles matrix originated from the plasma membrane or the golgi Result of the chromosomal anomaly Hybrid gene 5' CLTC - 3' ALK Description

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -569-

Fusion the 1634 N term amino acids from CLTC fused to the 562 C-term amino Protein acids from ALK (i.e. the entire cytoplasmic portion of ALK with the Description tyrosine kinase domain)

External links Other t(2;17)(p23;q23) Mitelman database (CGAP - NCBI) database Other t(2;17)(p23;q23) CancerChromosomes (NCBI) database Bibliography CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B. Blood 2000; 96: 3681-3695.

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG. Leukemia 2000; 14: 1533-1559.

Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Morris SW, Xue L, Ma Z, Kinney MC. Br J Haematol 2001; 113: 275-295. Medline 21275125

Contributor(s) Written 08- Jean-Loup Huret 2003

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -570-

Citation This paper should be referenced as such : Huret JL . t(2;17)(p23;q23). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0217p23q23ID1290.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -571- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;22)(p23;q11.2)

Clinics and Pathology Disease Anaplasic large cell lymphoma (ALCL): translocations involving 2p23 are found in more than half cases of anaplasic large cell lymphoma (ALCL), a high grade non Hodgkin lymphoma (NHL). They involve ALK, and are therefore called ALK+ ALCL. The most frequent ALK+ ALCL being the the t(2;5)(p23;q35) with NPM1 -ALK fusion protein, which localises both in the cytoplasm and in the nucleus. The t(2;22)(p23;q11) has so far been described in only 1 case, and, like other t(2;Var) involving various partners and ALK, the fusion protein has a cytoplasmic localization; they are therefore called "cytoplasm only" ALK+ ALCL. Clinics ALK+ ALCL without the t(2;5) (so called cytoplasmic only ALK cases) show clinical features similar to those of classical ALK+ ALCL: young age, male predominance, presentation with advanced disease, systemic symptoms, frequent involvement of extranodal sites, and a good prognosis. The t(2;22) case was that of a 12 yrs old girl. Genes involved and Proteins Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor Gene MYH9 Name Location 22q11.2 Protein codes for the non-muscle myosin II, heavy chain type A. Non-muscle myosin II is involved in motility and cell division Germinal in patients with May-Hegglin anomaly and Fechner syndrome mutations Somatic MYH9/ALK fusion protein in ALCL (see above) mutations Result of the chromosomal

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -572- anomaly Hybrid gene 5' MYH9 - 3' ALK Description

Fusion 2201 amino acids, 220 kDa. N term MYH9 fused to the 556 C-term Protein amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with Description the tyrosine kinase domain), instead of the classic 562 C-term amino acids from ALK seen in other ALK fusion proteins

External links Other t(2;22)(p23;q11.2) Mitelman database (CGAP - NCBI) database Other t(2;22)(p23;q11.2) CancerChromosomes (NCBI) database Bibliography CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B. Blood 2000; 96: 3681-3695.

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG. Leukemia 2000; 14: 1533-1559.

Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Morris SW, Xue L, Ma Z, Kinney MC. Br J Haematol 2001; 113: 275-295. Medline 21275125

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -573-

Contributor(s) Written 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(2;22)(p23;q11.2). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0222p23q11D1291.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -574- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(16;21)(q24;q22)

Identity

t(16;21)(q24;q22) G-banding (top left) - Courtesy Jean Luc Laï; R-banding (middle left - Courtesy Jean Luc Laï and top and middle right - Courtesy Pascale Cornillet- Lefebvre and Stéphanie Struski). Fish studies: chromosome 16 and 21 paints; AML1 probe: the 2 chromosomes 21 and the der(16) are labelled (below) - Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski.

Clinics and Pathology Disease Myelodysplastic syndromes (MDS) and acute non lymphocytic leukemias (ANLL) and therapy related ANLL Phenotype / cell stem M1 or M2 ANLL origin Etiology 11 of 15 cases have had treatment for a previous malignancy (treatment related MDS or ANLL (t-MDS/ANLL)). Previous disease was a breast cancer in 5 cases, a hematologic malignancy in 4. Epidemiology 15 available cases at least, sex ratio: 2M / 13F; mediane age around 50 yrs (range <15 - 62) Clinics blood data: pancytopenia Prognosis poor

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -575- Cytogenetics Additional + 8 found in 7 of 15 cases anomalies Genes involved and Proteins Gene CBFA2T3 (MTG16) Name Location 16q24 Protein member of the ETO (MTG8) family Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes. Result of the chromosomal anomaly Hybrid gene 5' AML1 - 3' CBFA2T3 Description

External links Other t(16;21)(q24;q22) Mitelman database (CGAP - NCBI) database Other t(16;21)(q24;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Cytogenetics of childhood acute nonlymphocytic leukemia. Raimondi S, Kalwinsky DK, Hayashi Y, et al. Cancer Genet Cytogenet 1989; 40: 13-27.

Metaphase fluorescence in situ hybridization (FISH) in the follow-up of 60 patients with haematopoietic malignancies. Nylund SJ, Ruutu T, Saarinen U, Knuutila S, et al.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -576- Br J Haematol 1994; 88: 778-783 .

Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non-Hodgkin's lymphoma. Traweek ST, Slovak ML, Nademanee AP, Brynes RK, Niland JC, Forman SJ. Blood 1994; 84: 957-963.

Secondary acute myeloblastic leukemia with t(16;21)(q24;q22) involving the AML1 gene. Berger R, Le Coniat M, Romana SP, Jonveaux P. Hematol Cell Ther 1996; 38: 183-186.

A recurrent translocation, t(16;21)(q24;q22), associated with acute myelogenous leukemia: identification by fluorescence in situ hybridization. Shimada M, Ohtsuka E, Shimizu T, Matsumoto T, Matsushita K, Tanimoto F, Kajii T Cancer Genet Cytogenet. 1997; 96: 102-105. Medline 97359798

The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8 (ETO) family. Gamou T, Kitamura E, Hosoda F, et al. Blood 1998; 91: 4028-4037.

A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. Takeda K, Shinohara K, Kameda N, et al. Int J Hematol 1998; 67: 179-186

AML1-MTG16 fusion gene in therapy-related acute leukemia with t(16;21)(q24;q22): two new cases. Salomon-Nguyen F, Busson-Le Coniat M, Lafage-Pochitaloff M, et al. Leukemia 2000; 14: 1704-1705.

21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. Genes Chromosomes Cancer 2002; 33: 379-394. Medline 11921272

Contributor(s) Written 04- Christine Pérot 1998 Updated 08- Jean-Loup Huret

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -577- 2003 Citation This paper should be referenced as such : Pérot C . t(16;21)(q24;q22). Atlas Genet Cytogenet Oncol Haematol. April 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1621ID1123.html Huret JL . t(16;21)(q24;q22). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1621ID1123.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -578- Atlas of Genetics and Cytogenetics in Oncology and Haematology

15q13-15 Rearrangements

Clinics and Pathology Disease Acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CML), chronic lymphocytic leukemia (CLL) and non Hodgkin lymphomas (NHL). Phenotype / Most ALL are B-lineage, few T-lineage. cell stem AML: most subtypes. origin CML: Lymphomas: described in follicular, diffuse large B-cell, mantle cell and anaplastic large cell, as well as Hodgkin lymphomas. Epidemiology Rare in childhood ALL (about 1%), more common in infant ALL (about 13%). Very rare in AML, adult ALL, CLL and lymphomas. Occurs in primary and secondary leukemias. CML: rare, occurs as secondary abnormality or part of complex Ph rearrangement Prognosis Childhood ALL: No increased risk with current treatment regimens. Outcome not described in other diseases. Cytogenetics Additional Various anomalies result in 15q13-15 breakpoints, most frequently anomalies balanced translocations, but also unbalanced translocations and deletions. Childhood ALL: 15q13-15 breakpoints frequently occur in complex karyotypes. Associated abnormalities of 9p and of 12p 12p, as well as t(9;22)(q34;q11.2) are common. 15q13-15 breakpoints also have been reported with der(19)t(1;19)(q21;q13). A t(5;15)(p15.1 or p15.3;q11 or q13) occurs primarily in infant ALL, although also was reported in one adolescent ALL. AML: found as primary abnormality and as secondary abnormality, with various other abnormalities including t(9;22)(q34;q11.2), t(8;21)(q22;q22), as well as part of complex rearrangements with 8q22 and 21q22. Recurrent aberrations are: t(11;15)(q23;q14) reported in both AML and ALL and t(12;15)(p12-13;q13-15) in AML. CML: occurs in variant Ph and in secondary abnormalities. Bibliography Mitelman Database of Chromosome Aberrations in Cancer (2003). Mitelman F, Johansson B and Mertens F (Eds.)

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -579- http://cgap.nci.nih.gov/Chromosomes/Mitelman

Abnormalities of Chromosome Bands 15q13-15 in Childhood Acute Lymphoblastic Leukemia. Heerema NA, Sather HN, Sensel MG, Hutchinson RJ, Nachman JB, Reaman GH, Lange BJ, Steinherz PG, Bostrom BC, Gaynon PS, Uckun FM. Cancer 2002; 94:1102-1110. Medline 11920481

Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia (ALL): impact of the 11q23 breakpoint on outcome. A report of the Children¹s Cancer Group. Heerema NA, Arthur DC, Sather H, Albo V, Feusner J, Lange BJ, Steinherz PG, Zeltzer P, Hammond D, Reaman GH. Blood 1994; 83: 2274-2284. Medline 8161794

Contributor(s) Written 09- Nyla A Heerema 2003 Citation This paper should be referenced as such : Heerema NA . 15q13-15 Rearrangements. Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/15q13rearID1257.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -580- Atlas of Genetics and Cytogenetics in Oncology and Haematology

+18 or trisomy 18 in lymphoproliferative disorders

Clinics and Pathology Note Trisomy 18 seen with other abnormalities is fairly nonspecific, having been reported in most lymphoproliferative disorders. Trisomy 18 as a sole abnormality is also nonspecific, having been reported in MDS, AML, ALL (14 cases), lymphoma (3 of 6 reported cases were follicular lymphoma), Hodgkin's disease (two cases) and CLL (10 cases). Disease Acute lymphocytic leukemia (ALL) Note Trisomy 18 is common in hyperdiploid ALL with more than 50 chromosomes (15-27% of cases). The great majority of karyotypes with trisomy 18 also exhibit trisomy 4, 6, 10, and 14, either trisomy 21 or tetrasomy 21, and an extra X chromosome. More than half either have trisomy 17 or an isochromosome 17q. It is unusual to see trisomy 18 in a hyperdiploid ALL with fewer than 50 chromosomes. It is likewise unusual to find trisomy 18 associated with one of the common structural changes in ALL, such as the 1;19. However, at least two hyperdiploid ALL cases have been reported with trisomy 18 and tetrasomy 21 in which a t(12;21) was detected by FISH analysis; further research is indicated. Epidemiology Of 14 reported ALL cases with trisomy 18 as the sole cytogenetic abnormality, nine were reported from India. Is there an environmental component to this unusual distribution of cases? Prognosis The prognosis appears to be neutral to favorable in a karyotype with >51 chromosomes that includes trisomy 18. There is some evidence of an unfavorable prognosis if the karyotype is isolate trisomy 18.

Disease Multiple myeloma Note Trisomy 18 is observed in roughly 10% or multiple myeloma (MM) karyotypes. In MM with trisomy 18, the karyotype is usually hyperdiploid (49-60 chromosomes) with multiple trisomies, tetrasomies, and structural abnormalities. The most common structural anomalies that appear with trisomy 18 are chromosome 1 rearrangements (30%) and 14q32 rearrangements (25%) about half of which are t(11;14). The most common trisomies (25-35%) are: +3, +5, +6, +9, +11, and +15, with less frequent (10-20%) trisomy 1, 10, 14, and 17, and monosomy 8. Prognosis No correlation between trisomy 18 and prognosis

Disease Hodgkin's disease.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -581- Note Trisomy 18 in Hodgkin's disease has been reported in a few quite complex near-triploid karyotypes (59-83 chromosomes, and in hyperdiploid karyotypes with simple trisomies and only an occasional chromosome rearrangement. Among these latter cases are two with isolated trisomy 18, and others with up to 52 chromosomes and common recurrence of trisomies 2, 7, 12, and 21. Cytology The Hodgkin's disease cases with trisomy 18 have included both the mixed cellularity and the nodular sclerosis types.

Disease Chronic lymphocytic leukemia. Note Trisomy 18 is very uncommon in CLL. When observed, it usually presents as the sole abnormality, or with a karyotype of 49,+12, +18,+19. The karyotype is occasionally more complex. Epidemiology Of CLL cases reported with trisomy 18, about 15% exhibited apparently independent cytogenetically abnormal cell populations, with isolated trisomy 18 as one of two, three, or more clones. The clinical significance of these clones is not understood.

Disease Non-Hodgkin's lymphoma. Note Trisomy 18 is observed in 15-33% of lymphomas, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone B-cell lymphoma (MZBCL). Trisomy 18 may be less frequent in other NHL sub-types.

Trisomy 18 is strongly associated with a t(14;18) or at least a 14q32 abnormality, and may represent a variant of the +der(18)t(14;18), which duplicates the segment 18pter-18q21. Trisomy 18 is rarely observed as the primary cytogenetic change in NHL.

• In DLBCL, the karyotype with trisomy 18 is usually hyperdiploid with 47-52 chromosomes and with multiple chromosome rearrangements. Trisomy 3 accompanies trisomy 18 in about 30% of cases, and trisomies 7, 12, and 21 in about 10% each. About 10% have a t(14;18) or +der(18)(t(14;18), about 5% have a t(8;14), and another 10% have another 14q32 rearrangement. About 20% have a 6q rearrangement or an i(6)(p10) that results in loss of 6q, and about 20% have an extra X chromosome, many of which are structurally abnormal.

• In FL, the general cytogenetic pattern of cases with trisomy 18 is similar to that of DLBCL. The principle difference is that about 75% of cases exhibit a t(14;18) or an add(14)(q32), and association of trisomy 18 and a t(8;14) is very uncommon.

• Trisomy 18 is a recurrent finding in MZBCL, seen in 39% of cases in one study. About a third of marginal zone lymphomas with trisomy 3 also exhibit trisomy 18.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -582- • About 10% of peripheral T-cell lymphomas exhibit trisomy 18, and then usually as part of a fairly complex karyotype.

Phenotype / Overexpression of BCL2 has been reported in trisomy 18 without cell stem t(14;18). CGH studies suggest duplication 18q (which would include origin trisomy 18) tend to occur early in the cytogenetic evolution. In FL, 18q gains were most common in young males and occurred with similar frequency in FL with and without t(14;18). Prognosis Trisomy 18 as a secondary abnormality in NHL has no significant influence on tumor grade or overall survival.

External links Other +18 or trisomy 18 in lymphoproliferative Mitelman database (CGAP - database disorders NCBI) Bibliography Chromosomal abnormalities in indolent lymphoma. Speaks SL, Sanger WG, Linder J, Johnson DR, Armitage JO, Weisenburger D, Purtilo D. Cancer Genet Cytogenet 1987; 27: 335-344. Medline 3297304

Prognostic signficance of karyotype analysis in children with acute lymphoblastic leukemia. Ankathil R, Stephen J, Vasudevan DM, Kusumakumary P, Pillai GR, Nair MK. Hematol Oncol 1992; 10: 339-344. Medline 1296934

Chromosomes in Hodgkin's disease - analysis of involved lymph nodes. Ankathil R, Vijayakuman T, Pillai GR, Nair MK. Neoplasma 1992; 39: 245-248. Medline 1436237

Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B- progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Harris MB, Shuster JJ, Carroll A, Look AT, Borowitz MH, Crist WM, Nitschke R, Pullen J , Steuber CP, Land VJ. Blood 1992; 79: 3316-3324. Medline 1596572

Phenotypic and genotypic characterization of Hodgkin's disease. Koduru PRK, Susin M, Schulman p, Catell D, Goh JC, Karp L, Broome JD. Am J Hematol 1993; 44: 117-124. Medline 8266916

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Clinical and morphological features of B-cell small lymphocytic lymphoma with del(6)(q21q23). Offit K, Louie DC, Parsa NZ, Filippa D, Gangi M, Siebert R, Chaganti RSK. Blood 1994; 83: 2611-2618. Medline 8167342

Prognostic value of chromosomal abnormalities in follicular lymphoma. Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, Bastard C. Blood 1994; 84: 1043-1049. Medline 8049424

Cytogenetic findings in 200 patients with multiple myeloma. Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cancer Genet Cytogenet 1995; 82: 41-49. Medline 7627933

Sequential analysis of 43 patients with non-Hodgkin's lymphoma: Clinical correlations with cytogenetic, histologic, immunophenotyping, and molecular studies. Whang-Peng J, Knutsen T, Jaffe ES, Steinberg SM, Raffeld M, Zhao WP, Duffey P, Condron K, Yano T, Longo DL. Blood 1995; 85: 203-216. Medline 7803794

Clinical implications of cytogenetic classification in adult acute lymphoblastic leukaemia patients. Ankathil R, Geetha N, Remani P, Gangadharan VP, Pillai GR, Nair MK. J Cancer Res Clin Olcol 1996; 122: 370-373. Medline 8642049

Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features. Dierlamm J, Pittaluga S, Wlodarska I, Stul M, Thomas J, Boogaerts M, Michaux L, Driessen A, Mecucci C, Cassiman J-J, de Wolf-Peeters C, van den Berghe H. Blood 1996; 87: 299-307. Medline 8547655

Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations. Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MT, Fraile A, Carrasco JL, Sole F, Cuesta B, Guillon A. Genes Chromosomes Cancer 1997 ;18 :84-93. Medline 9115968

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -584- Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Smadja NV, Fuchart C, Isnard F, Luvet C, Dutel JL, Cheron N, Grange MJ, Monconduit M, Bastard C. Leukemia 1998; 12: 960-969. Medline 9639426

Prognostic implications of cytogenetic aberrations in diffuse large B-cell lymphomas. Jerkeman M, Johansson B, Akerman M, Cavallin-Stahl E, Kristoffersson U, Mitelman F. J Haematol 1999; 62: 184-190. Medline 10089896

Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias. Andreasson P, Hoglund M, Bekassy AN, Garwicz S, Heldrup J, Mitelman F, Johansson B. Eur J Haematol 2000; 65: 40-51. Medline 10914938

Prognostic impact of trisomies of chromosomes 10, 17, and 5 aomong children with acute lymphoblastic leukemia and high hyperdiploidy (>50 chromosomes). Heerema NA, Sather HN, Sensel MG, Zhang T, Hutchinson RJ, Nachman JB, Lange BJ, Seeinherz PG, Bostrom BC, Reeaman GH, Gaynon PS, Uckun FM. J Clin Oncol 2000; 18: 1876-1887. Medline 10784628

Importance of using comparative genomic hybridization to improve detection of chromosomal changes in childhood acute lymphoblastic leukemia. Jarosova M, Holzerova M, Jedlickova K, Mihal V, Zuna J, Stary J, Pospisilova D, Zemanova Z, Trka J, Blazek J, Pikalova Z, Indrak K. Cancer Genet Cytogenet 2000; 123: 114-122. Medline 11156736

Follicular lymphoma with trisomy 18 and over-expression of BCL2 in the absence of t(14;18)(q32;q21). Wong KF, Chan JKC. Cancer Genet Cytogenet 2000; 123: 52-54. Medline 11120335

Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant. Mohamed AN, Palutke M, Eisenberg L, Al-Katib A. Cancer Genet Cytogenet 2001; 126: 45-51. Medline 11343778

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Detection of secondary genetic aberrations in follicle center cell derived lymphomas: assessment of the reliability of comparative genomic hybridization and standard chromosome analysis. Viardot A, Martin-Subero JI, Siebert R, Harder S, Gesk S, Bentz M, Schlegelberger B. Leukemia 2001; 15: 177-183. Medline 11243387

Clinicopathologic correlations of genomic gains and losses in follicular lymphoma. Viardot A, Moller P, Hogel J, Werner K, Mechtersheimer G, Ho AD, Ott G, Barth TFE, Siebert R, Gesk S, Schlegelberger B, Dohner H, Bentz M. J Clin Oncol 2002; 20: 4523-4530 Medline 12454108

Contributor(s) Written 09- Daniel L Van Dyke 2003 Citation This paper should be referenced as such : Van Dyke DL . +18 or trisomy 18 in lymphoproliferative disorders. Atlas Genet Cytogenet Oncol Haematol. September 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/Tri18ID2030.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -586- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Soft tissue tumors: Inflammatory myofibroblastic tumor

Identity Other atypical fibromyxoid tumor names pseudosarcomatous fibromyxoid tumor plasma cell granuloma pseudosarcomatous myofibrotic proliferation postoperative spindle cell nodules inflammatory pseudotumor Clinics and Pathology Disease rare soft tissue tumour of controversial nosology; at the edge between benign and malignant tumours, with a possible heterogeneity Epidemiology found in children and young adults Clinics occurs in the soft tissue and viscera; the tumour is localized in lungs, mesentery, retroperitoneum, and pelvis. Pathology spindle cell proliferation with myofibroblastic differenciation with a collagen stroma and an inflammatory infiltrate of lymphocytes, eosinophils, and plasma cells Treatment surgical excision Prognosis This tumour has an indeterminate or low malignant potential; tumour related deaths (occuring in less than 10% of cases) are due to local invasion, not to distant metastases Genetics Note about one 50 to 60 % of the cases present with a 2p23 rearrangement involving the gene ALK; this subset of tumours should have a different genetic background, and may have a different behaviour, in terms of epidemiology (younger age?), prognosis ... Cytogenetics Cytogenetics So far, t(1;2)(q25;p23), t(2;2)(p23;q13), t(2;11)(p23;p15), Morphological t(2;17)(p23;q23), and t(2;19)(p23;p13.1) have been described; the t(1;2)(q25;p23) with TPM3 involvement would be the most frequent. Genes involved and

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -587- Proteins Note these translocations involve ALK in 2p23, and either TPM3 in 1q25, CLTC in 17q23, or TPM4 in 19p13 Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor

Gene TPM3 (tropomyosin alpha chain) Name Location 1q25 Protein 284 amino acids, 33 kDa; coiled coil structure; role in Calcium dependant actin-myosin interaction

Gene RANBP2 Name Location 2q13 Protein 3224 amino acids, 358 kDa; nuclear pore protein involved in nuclear export

Gene CARS Name Location 11p15

Gene CLTC (clathrin heavy polypeptide) Name Location 17q23 Protein 1675 amino acids, 191 kDa; mediate endocytosis of transmembrane receptors.

Gene TPM4 (tropomyosin fibroblast, non muscle type) Name Location 19p13.1 Protein 248 amino acids, 29 kDa; coiled coil structure

Result of the chromosomal anomaly Hybrid Gene Description 5' partner - 3' ALK

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -588- Fusion

Protein Description N-term amino acids from the partner gene fused to the 562 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected.

To be noted ALK and some of the above ALK partners, or closely related genes, are found implicated both in anaplasic large cell lymphoma and in inflammatory myofibroblastic tumours; this is a new concept, that 2 different types of tumour may result from the same chromosomal/genes Bibliography Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Cancer Res 1999, 59: 2776-2780.

Aberrant ALK tyrosine kinase signaling. Different cellular lineages, common oncogen,ic mechanims? Ladanyi M. Am J Pathol 2000; 157: 341-345.

ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal mtofibroblastic fibrous lesion: toward a molecular definition of an inflammatory myofibroblastic tumor family? Sirvent N, Hawkins AL, Moeglin D, Coindre JM, Kurzenne JY, Michiels JF, Barcelo G, Turc-Carel C, Griffin CA, Pedeutour F. Genes Chromosom Cancer 2001; 31: 85-90.

Anaplastic lymphoma kinase (ALK)expression in the inflammatorymyofibroblastic tumor, a comparative immunohistochemical study.. Cook JR, Dehner LP, Collins MH, Ma Z, Morris SW, Coffin CM, Hill DA. Am J Surg Pathol 2001; 25: 1364-1371.

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REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08- Jean-Loup Huret 2001 Updated 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . Soft tissue tumors: Inflammatory myofibroblastic tumor. Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://AtlasGeneticsOncology.org/Tumors/MyofibroID5073.html Huret JL . Soft tissue tumors: Inflammatory myofibroblastic tumor. Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/MyofibroID5073.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -590- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Ovary: Germ cell tumors

Identity Note Ovarian germ cell tumours (OGCT) are a type of ovarian neoplasm principally affecting young women. They are derived from primitive germ cells of the embryonic gonad, and may undergo germinomatous or embryonic differentiation. They differ in clinical presentation, histology and biology, and include both benign (predominantly) and malignant subtypes. Germ cell tumours (GCT) account for 15-20% of all ovarian neoplasms, and constitute the second largest group of ovarian neoplasms. Less than 5% of ovarian cancers are of germ cell origin. Classification Note OGCT are subdivided into the clinicopathological entities listed in Table 1.

Note Table 1 Subtypes and characteristics of ovarian germ cell tumours (data derived from Rice, 1999 and John Hopkins Pathology, 2001).

Clinics and Pathology Etiology No factors have been associated with the aetiology of GCT, apart from

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -591- an increased incidence associated with dysgenetic gonads. 5% of patients with dysgerminomas are associated with constitutional cytogenetic abnormalities involving the entirety or part of the Y chromosome; 46,XY (testicular feminisation), gonadal dysgenesis and mixed gonadal dysgenesis (45,X, 46,XY). However 95% of females with dysgerminomas are cytogenetically normal. In genetic syndromes with a high risk of cancer, rarely are GCT found. GCT may be found infrequently in individuals with Li-Fraumeni. Epidemiology GCT predominantly affect young women, but they do sometimes occur in infants and older women. GCT account for over 60% of ovarian neoplasms in children and adolescents, one-third of which are malignant. The frequency of OGCT is invariable throughout the world. There does not appear to be a racial predisposition, in contrast to epithelial ovarian cancers. The incidence of OGCT increases in incidence from the age of 8-9 years, and peaks at 18 years (20 per million). The mean age of presentation of OGCT is 19 years. The incidence of OGCT is much lower than that of testicular germ cell tumours (TGCT). At 19 years of age the incidence of GCT in males is 44.5 per million, whereas it is only 10.4 per million in females. In the US, the incidence of GCT has not increased during the last thirty years. Clinics Most GCT are benign and unilateral, with the exception of dysgerminomas. Patients usually present at stage I. Abdominal pain or adnexal torsion is the commonest presenting symptom of GCT, however they may be asymptomatic. The mass may cause acute pain due to torsion, rupture, or haemorrhage. Patients may also have abdominal distension, vaginal bleeding or fever. Teratomas are usually diagnosed in premenopausal women without presenting symptoms. Complications of mature cystic teratoma (dermoid cyst) include torsion, rupture, infection and haemolytic anaemia. Approximately 50% of prepubertal girls with nongestational choriocarcinoma are isosexually precocious. Only 1-2% of dermoid cysts become malignant, usually in postmenopausal women. Patients with ESTs frequently present following spontaneous rupture and haemorrhage. Pathology Teratomas Teratomas develop from totipotential germ cells, and consequently contain all three germ cell layers: ectoderm, mesoderm and endoderm. Teratomas are classified into immature (malignant), mature (dermoid cyst) and monodermal (struma ovarii, carcinoid). Dermoid cysts contain mature tissue, and upon gross examination skin, teeth, bone, hair, sebaceous glands and neural tissue predominate; whilst cartilage, respiratory and intestinal epithelium are also common. They are cystic tumours with a firm capsule. Monodermal teratoma comprise mainly one tissue element. For example the most common type of monodermal teratoma, Struma ovarii, is comprised of at least 50% mature thyroid tissue (of any type). Argentaffin cells in dermoid cysts are usually the site of origin for ovarian carcinois, although this is rare. Immature teratomas account for approximately 20% of all

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -592- malignant GCT. They are classified as Grade I, II or III if they have 0 or1, 3 or less, or 4 or more low-power fields (x-40) containing immature neuroepithelium per section, respectively. Immature teratomas are solid tumours containing immature or embryonal tissues. Immature neuroepithelium is the predominant immature tissue found. Dysgerminoma Dysgerminomas have a solid, lobulated, tan, flesh-like gross appearance with a smooth surface. Microscopically dysgerminoma cells are round and ovoid, contain abundant cytoplasm, irregularly shaped nuclei, >1 prominent nucleolus. These cells have a propensity to aggregate forming cords and sheets. Lymphocytic and granulocytic infiltration of the fibrous septa are often evident. Endodermal Sinus Tumor (EST) Gross examination of EST, also known as yolk sac tumour, demonstrate smooth, glistening, hemorrhagic and necrotic surfaces. Histology reveals a wide range of patterns (microcystic, endodermal sinus, solid, alveolar-glandular, papillary, macrocystic, hepatoid, primitive endodermal). The classic pattern contains Schiller-Duval bodies (central capillary surrounded by simple papillae) and eosinophilic globules containing AFP. Intracellular and extracellular hyaline droplets (periodic acid-Schiff positive) are also seen in EST. Embryonal Carcinoma Gross examination of embryonal carcinoma reveals a solid, haemorrhagic, necrotic tumour, resembling a larger form of EST. Embryonal glands, glandlike clefts (embryoid bodies), and syntrophoblastic giant cells are present microscopically. Choriocarcinoma Choriocarcinoma is a very rare solid, haemorrhagic tumour, composed of malignant cytotropohoblast and syncytiotrophoblast. Nongestational and gestational choriocarcinoma have identical histologies. Mixed Germ Cell Tumour As the name suggests, mixed germ cell tumours contain >1 histological type. Dysgerminoma with EST, and immature teratomas with EST are frequent combinations. Polyembryoma Histological analysis of polyembryoma demonstrates erythroid bodies in different stages of presomite development. Treatment The treatments used for OGCT have largely been based on those used for the more prevalent TGCT. In young patients surgery should be conservative in order to preserve fertility. Consequently unilateral salpingo-oophorectomy is performed for all stages of dysgerminatous and nondysgerminatous GCT. Even if extra-ovarian disease is present, the contralateral ovary and uterus should not be removed as these tumours are curable with chemotherapy. However if fertility is not of concern, total abdominal hysterectomy and bilateral salpingo-oophorectomy, together with removal of as much tumour tissue as possible, is recommended for stage II, III and IV of dysgerminatous and nondysgerminatous GCT. Chemotherapy is preferable, despite these tumours being highly radiosensitive (except EST and embryonal carcinoma), in order to

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -593- preserve ovarian function. All patients irrespective of tumour histology, except those with immature teratomas (stage IA, grade1), receive post-operative chemotherapy, for adjuvant or curative purposes. Adjuvant chemotherapy is given to patients with completely resected stages I, II or III ESTs, mixed cell tumours, embryonal carcinomas, choriocarcinomas and immature teratomas due to high recurrence rates. All non-dysgerminomatous GCT receive the same chemotherapy regimes based on a combination cisplatin therapy. Combination therapies include vinblastine, bleomycin, and cisplatin (VBP); bleomycin, etoposide and cisplatin (BEP) and also etoposide and cisplatin (EP). Combination chemotherapy is given to patients with bulky residual disease, extra abdominal metastases, or those who failed primary treatment with a curative intent. Survival rates for nondysgerminatous ovarian germ cell malignancies has increased dramatically with the use of platinum-based combination chemotherapy. Approximately 15-25% of dysgerminomas recur, but these are usually treated with a curative outcome. The survival rates for dysgerminomas presenting at early and advanced stages are 95% and >80% respectively. The survival rates for stage I and II ESTs are reported to be 60- 100%, whereas for those with stage III or IV disease the prognosis is less favourable (50-75%). Survival rates for embryonal carcinoma are slightly higher than those for ESTs. The prognosis of immature teratomas is governed by grade and stage. Grade 1, stage 1 have 100% survival rate, whereas stage III, grade 1 have only a 50% chance of survival. Meanwhile, most patients with mature teratomas show long survival times. The prognosis is better for gestational choriocarcinoma than nongestational carcinoma. The prognosis for mixed GCT is dictated by the proportion of the more malignant component and the stage. Evolution The means by which OGCT metastasise are summarised in Table 1. Dysgerminomas are the only type of ovarian tumour to metastasise lymphatically. Malignant degeneration of 1-2% of mature teratomas occurs, usually into squamous cell carcinoma. Prognosis The prognosis of OGCT is excellent, as most cases are benign. When malignant they are very aggressive, but the prognosis is still good provided it is treated without delay with combination chemotherapy. Genetics Note There have been several published reports of ovarian germ cell cancers affecting more than one family member. The rarity of these cancers, (lifetime risk is 0.07%), and the close relationships between affected individuals suggests that a susceptibility gene to germ cell malignancies may be responsible in some families. In addition, several cases of families with both males and females diagnosed with germ cell malignancies have been published, suggesting a common genetic aetiology and susceptibility. Linkage analysis of familial TGCT has

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -594- identified Xq27. Cytogenetics Cytogenetics There is a paucity of cytogenetic data available on OGCT. Of 25 Morphological mature and immature teratomas displaying abnormal karyotypes, 16 had numerical changes only. Trisomy 3, 8, 12 and 14 were the most common numerical changes identified. Isochromosome 12p, i(12p) is the only recurrent structural rearrangement in OGCT, particularly in dysgerminomas and malignant GCT with a yolk sac component. I(12p) is more prevalent in TGCT, present in 80% of all such tumours. The presence of this anomaly in both testicular and ovarian GCT suggests that they may arise from a similar pathogenesis process. A representative example of isochromosome 12p, i(12p), is shown in Testicular Germ Cell tumor. Interphase cytogenetics using a chromosome 12 centromere and a 12p locus-specific probe can be used to detect this abnormality. Trisomy 12 has been found in several immature teratomas, supporting the importance of this chromosome in the onset of a subset of OGCT.

Immature teratomas frequently have chromosomal abnormalities (63%), of which gains of chromosomes 3, 8, 12 and 14, losses of chromosomes 4 and 13, and several structural rearrangements including i(12p) are common. It has been proposed that cytogenetically abnormal immature teratomas are more likely to recur than their cytogenetically normal counterparts.

Over 300 mature teratomas have undergone cytogenetic analysis and only 4% have had aberrant karyotypes, displaying numerical alterations only, none of which are recurrent. The few cases in which abnormalities have been identified were as follows: trisomy of chromosome 8 (2 cases), 13 (1 case), 15 (1 case), 20 (1 case) and double trisomy of chromosomes 7 and 12; losses of chromosomes 3, 6, 7, 11, 16, 17, 21 and 22; structural rearrangements involving +mar (2 cases), add(1)(q11) (1 case), der(6)(t1;6)(q11q22) (1 case), i(12)(p10) (1 case) and +del(20)(q11) (1 case).

Mature teratomas that have undergo malignant transformation display multiple numerical and structural chromosomal anomalies principally involving chromosomes X, 1, 3, 4, 5, 9, 10 and 11. Several similarities were found when comparing the benign cystic and malignant component of an ovarian teratoma. It is noteworthy that the benign component had multiple anomalies (13 non-random structural and numerical changes), which raises the possibility that multiple anomalies in the benign component predispose the tumour to malignant transformation.

Complex numerical and structural chromosome changes were apparent in mixed mesodermal tumors, but there is insufficient data to address whether this tumour subtype has a different composition of chromosomal abnormalities than the other subtypes. Abnormalities of

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -595- chromosome 12 were found in two of six cases of ovarian choriocarcinomas. Monosomy 22 was identified as the sole anomaly in a mixed germ cell-sex cord stromal tumour in the ovary, by both karyotyping and CGH, which may suggest a common pathogenetic mechanism for both tumour types.

From the cytogenetic data available to date, it appears that similarities exist between OGCT and TGCT. Isochromosome 12p, i(12p), gains of chromosomes 1, 8, 21 and loss of chromosomes 6 and 13 have been reported in both. Cytogenetics There have only been a limited number of studies employing Molecular comparative genomic hybridisation (CGH) to investigate OGCT, and no allelotype studies have been undertaken.

27 ovarian GCT were analysed by CGH, of which 12 were dysgerminomas, 6 were ESTs, 3 were mixed GCT and the remainder were immature teratomas. The data was grouped for the dysgerminomas, ESTs and mixed GCT and the most frequent finding was gain of 12p, (14/19), 8 of which showed gain of 12p only, (which may result from i(12p)), 4 showed gains of the entirety of chromosome 12 and 2 showed high level amplification of 12p11-p12. 12p gain is a frequent finding in TGCT, and amplification of 12p11-p12 has also been found in a few such cases. Other recurrent abnormalities were found in this group which have also been previously reported as recurrent findings in TGCT. These include gain of entire chromosome 21 (42 % of malignant OGCT vs. 45% TGCT), gain of chromosome 8 (42% OGCT vs. 45% TGCT), gain of 1q (32% OGCT vs. 36 TGCT) and loss of chromosome 13 (26% OGCT vs. 38% TGCT). There did not appear to be a correlation between the pattern of chromosomal imbalances and histological subtype, except for distal 1p deletion, which was exclusively found in two ESTs. Meanwhile, only 1 of the 6 immature teratomas revealed an abnormality, gain of chromosome 14.

A study summarised these findings according to histological entity. Every dysgerminoma (n=12) analysed showed chromosomal imbalances, with an average number of 10 changes per case. Gains were more common than losses. The most frequent anomalies were gains of 12p (8/12), 12q (9/12), 21q (8/12), 22q (7/12), 20q (6/12), 15q (5/12), 1p (4/12) and 6p (4/12) and the whole of chromosomes 19 (6/12), 7 (5/12), 8 (5/12) and 17 (5/12). Losses of chromosome 13 were seen in 7/12 of the cases. All 4 ESTs analysed displayed copy number changes, with an average of 6 per case. These included gain of 12p (3/4), 1q (3/4), 3p (2/4), 11q (2/4), Xp (2/4), and loss of 18q (2/4). Fewer changes were observed in the immature teratomas, with an average of 1.4 per case. 4 of the 9 immature teratomas had no copy number change. Gain of all or parts of 1p, 16p, 19 and 22 were identified in 2 of the cases with anomalies.

Thus both studies frequently found 12p gains in several subtypes of

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -596- OGCT, except for immature teratomas, and suggest that immature teratomas follow a different pathway to that taken by other malignant OGCT (and TGCT).

Several interphase cytogenetic studies have been performed on paraffin sections using centromeric probes to determine the copy number of chromosomes, and probes specifically designed to identify the i(12p). A study showed over-representation of chromosomes 7 and 12, and under-representation of chromosome 18, all of which are characteristic features in the male counterpart testicular seminoma. Genes involved and Proteins Note There is very little data available on the molecular mechanisms involved in the initiation and progression of OGCT. However, TGCT have undergone more extensive analyses. TGCT and OGCT have very similar pathological, biological, and cytogenetic features, thus it is highly likely that the genes involved are similar. To date, no gene has been unambiguously identified to be involved in the initiation or progression of TGCT. Several genes including KRAS2, JAW1 and SOX5 have been suggested as the candidate genes on 12p in TGCT. The candidate genes were searched in the 12p11.2p12.1 amplicon, and suggested that DAD-R is the most likely candidate. Overexpression of BCAT1, CMAS, EKI1, KRAS2 and SURB7 was demonstrated in a series of TGCT. LOH of regions frequently involved in TGCT is looked, in a panel of 35 OGCT. The results showed LOH of 3q27-q28 (50%), 5q31 (33%), 5q34-q35 (46%), 9p22-p21 (32%) and 12q22 (53%), and were found in all subtypes of OGCT. These data suggest that these loci may be harbouring tumour suppressor genes involved in the initiation and progression of OGCT and TGCT.

Ovarian teratomas develop in transgenic mice lacking a functional c- mos proto-oncogene. However, analysis of twenty teratomas for mutations of c-MOS did not identify any, suggesting that mutations of c- MOS do not play a significant role in the development of human ovarian teratomas.

Amplification of MYCN was found in 3/3 immature teratomas, but in 0/5 dermoid cysts and 0/5 mature teratomas. Less than 3% of GCT have mutations of p53. A somatic novel missense mutation (G to C at nucleotide 2467) of c-KIT has been identified in one ovarian mixed dysgerminoma/EST, which resulted in constitutive activation of KIT kinase activity.

There has been a single report of a germline BRCA1 mutation in a 16 year-old woman with dysgerminoma. This mutation was present in numerous relatives with different cancers including breast and ovarian cancer. It is unclear whether the dysgerminoma was a consequence of the germline mutation, or whether germline BRCA1 mutations are responsible for a small proportion of dysgerminomas and other types of

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -597- OGCT.

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Chromosomal abnormalities in choriocarcinomas of the female. Rodriguez E, Melamed J, Reuter V, Chaganti RS. Cancer Genet Cytogenet 1995; 80(1): 9-12. Medline 7697645

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Familial predisposition to both male and female germ cell tumours? Huddart RA, Thompson C, Houlston R, Nicholls EJ, Horwich A. J Med Genet 1996; 33(1): 86. Medline 8825060

Detection of chromosomal DNA gains and losses in testicular germ cell tumors by comparative genomic hybridization. Korn WM, Oide Weghuis DE, Suijkerbuijk RF, Schmidt U, Otto T, du Manoir S, Geurts van Kessel A, Harstrick A, Seeber S, Becher R. Genes Chromosomes Cancer 1996; 17(2): 78-87. Medline 8913724

Comparative genomic hybridization of germ cell tumors of the adult testis: confirmation of karyotypic findings and identification of a 12p-amplicon. Mostert MM, van de Pol M, Olde Weghuis D, Suijkerbuijk RF, Geurts van Kessel A, van Echten J, Oosterhuis JW, Looijenga LH. Cancer Genet Cytogenet 1996; 89(2): 146-152. Medline 8697422

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Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas. de Foy KA, Gayther SA, Colledge WH, Crockett S, Scott IV, Evans MJ, Ponder BA. Br J Cancer 1998; 77(10): 1642-1644. Medline 9635841

P53 tumour suppressor gene and germ cell neoplasia. Lutzker SG. Apmis 1998; 106(1): 85-89. Medline 9524566

Trisomy 3 as the sole karyotypic change in a pediatric immature teratoma. Mertens F, Kullendorff CM, Hjorth L, Alumets J, Mandahl N. Cancer Genet Cytogenet 1998; 102(1): 83-85. Medline 9530347

Genetic analysis of ovarian germ cell tumors by comparative genomic hybridization. Riopel MA, Spellerberg A, Griffin CA, Perlman EJ. Cancer Res 1998; 58(14): 3105-3110. Medline 9679978

Ovarian mature cystic teratoma with malignant transformation. An interphase cytogenetic study. Shen DH, Khoo US, Xue WC, Cheung AN. Int J Gynecol Pathol 1998; 17(4): 351-357. Medline 9785136

Cytogenetics of a malignant ovarian germ-cell tumor. van Echten J, van Doorn LC, van der Linden HC, van der Veen AY, Burger CW, de Jong B. Int J Cancer 1998; 77(2): 217-218. Medline 9650555

The Ovary. Rice LW. In Kistner's Gynecology & Women's Health 1999, Ryan KJ (ed): 166-189. Mosby.

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Activating c-kit gene mutations in human germ cell tumors. Tian Q, Frierson HF, Jr., Krystal GW, Moskaluk CA.

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Molecular genetic analysis of malignant ovarian germ cell tumors. Faulkner SW, Friedlander ML. Gynecol Oncol 2000; 77(2): 283-288. Medline 10785479

DNA copy number changes in malignant ovarian germ cell tumors. Kraggerud SM, Szymanska J, Abeler VM, Kaern J, Eknaes M, Heim S, Teixeira MR, Trope CG, Peltomaki P, Lothe RA. Cancer Res 2000; 60(11): 3025-3030. Medline 10850452

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours. Rapley EA, Crockford GP, Teare D, Biggs P, Seal S, Barfoot R, Edwards S, Hamoudi R, Heimdal K, Fossa SD, Tucker K, Donald J, Collins F, Friedlander M, Hogg D, Goss P, Heidenreich A, Ormiston W, Daly PA, Forman D, Oliver TD, Leahy M, Huddart R, Cooper CS, Bodmer JG, Easton DF, Stratton MR, Bishop DT. Nat Genet 2000; 24(2): 197-200. Medline 10655070

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Primary ovarian dysgerminoma in a patient with a germline BRCA1 mutation. Werness BA, Ramus SJ, Whittemore AS, Garlinghouse-Jones K, Oakley-Girvan I, DiCioccio RA, Tsukada Y, Ponder BA, Piver MS. Int J Gynecol Pathol 2000; 19(4): 390-394. Medline 11109172

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Chromosome analysis and comparison of the benign cystic and malignant squamous component of an ovarian teratoma.

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Genetic analysis of childhood germ cell tumors with comparative genomic hybridization. Schneider DT, Schuster AE, Fritsch MK, Calaminus G, Harms D, Gobel U, Perlman EJ. Klin Padiatr 2001; 213(4): 204-211. Medline 11528555

Genomic and expression analysis of the 12p11-p12 amplicon using EST arrays identifies two novel amplified and overexpressed genes. Bourdon V, Naef F, Rao PH, Reuter V, Mok SC, Bosl GJ, Koul S, Murty VV, Kucherlapati RS, Chaganti RS. Cancer Res 2002; 62(21): 6218-6223. Medline 12414650

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Comprehensive cytogenetic evaluation of a mature ovarian teratoma case. Schmid-Braz AT, Cavalli LR, Cornelio DA, Wuicik L, Ribeiro EM, Bleggi-Torres LF, Lima RS, de Andrade Urban C, Haddad BR, Cavalli IJ. Cancer Genet Cytogenet 2002; 132(2): 165-168. Medline 11850083

Ovarian Dysgerminomas Wu AY, Michener CM, Dellinger C, Barnes A. http://www.emedicine.com/med/topic601.htm 2002.

Germ cell, trophoblastic and other gonadal neoplasms ICCC X. Bernstein L, Smith MA, Liu L, Deapen D, Friedman DL. National Cancer Institute SEER Pediatric Monograph 2003: 125-137.

Role of gain of 12p in germ cell tumour development. Looijenga LH, Zafarana G, Grygalewicz B, Summersgill B, Debiec-Rychter M, Veltman J, Schoenmakers EF, Rodriguez S, Jafer O, Clark J, van Kessel AG, Shipley J, van Gurp RJ, Gillis AJ, Oosterhuis JW. Apmis 2003; 111(1): 161-171; discussion 172-163. Medline 12752258

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Ovarian Germ Cell Tumours. National Cancer Institute 2003.

Expression profile of genes from 12p in testicular germ cell tumors of adolescents and adults associated with i(12p) and amplification at 12p11.2- p12.1. Rodriguez S, Jafer O, Goker H, Summersgill BM, Zafarana G, Gillis AJ, van Gurp RJ, Oosterhuis JW, Lu YJ, Huddart R, Cooper CS, Clark J, Looijenga LH, Shipley JM. Oncogene 2003; 22(12): 1880-1891. Medline 12660824

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08- Lisa Lee-Jones 2003 Citation This paper should be referenced as such : Lee-Jones L . Ovary: Germ cell tumors. Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/OvarianGermCellID5067.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -606- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;2)(p23;q13)

Clinics and Pathology Disease Inflammatory myofibroblastic tumors (IMT) Clinics rare soft tissue tumour found in children and young adults Pathology spindle cell proliferation with myofibroblastic differenciation and an inflammatory infiltrate; staining of ALK-positive cases, representing 60% of IMT cases, is usually confined to the cytoplasm, but it showed a nuclear membran pattern in one of the two t(2;2) available cases Prognosis Inflammatory myofibroblastic tumors have a low malignant potential and good prognosis; however, the 2 cases with a t(2;2) showed (relatively) aggressive clinical course with tumor recurrence and round cell transformation Genes involved and Proteins Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor

Gene RANBP2 Name Location 2q13 Protein 3224 amino acids; nuclear pore protein involved in nuclear export

Result of the chromosomal anomaly Hybrid Gene Description 5' RANBP2 - 3' ALK Fusion

Protein Description 1430 amino acids; 6867 N-term amino acid from RANBP2, fused to the 562 C-term amino acids from ALK (i.e. the leucine-rich domain,

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -607- including the leucine zipper, of RANBP2 and the entire cytoplasmic portion of ALK with the tyrosine kinase domain). Oncogenesis the leucine zipper of RANBP2 could mediate oligomerization of RANBP2-ALK

Bibliography

Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Cancer Res 1999, 59: 2776-2780.

Aberrant ALK tyrosine kinase signaling. Different cellular lineages, common oncogen,ic mechanims? Ladanyi M. Am J Pathol 2000; 157: 341-345.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(2;2)(p23;q13). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/t0202p23q13ID5214.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -608- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;11)(p23;p15)

Clinics and Pathology Disease Inflammatory myofibroblastic tumors Clinics rare soft tissue tumour found in children and young adults Pathology spindle cell proliferation with myofibroblastic differenciation and an inflammatory infiltrate Cytogenetics The translocation was found complex: t(2;11;2)(p23;p15;q31) Prognosis low malignant potential and good prognosis Genes involved and Proteins Gene ALK Name Location 2p23 Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor

Gene CARS Name Location 11p15 Protein 748 amino acids, 85 kDa. Forms homodimers

Result of the chromosomal anomaly Hybrid Gene Description 5' CARS - 3' ALK Fusion

Protein Description 606 N-term amino acid from CARS, fused to the 562 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain).

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -609- Bibliography

Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Cancer Res 1999, 59: 2776-2780.

Aberrant ALK tyrosine kinase signaling. Different cellular lineages, common oncogen,ic mechanims? Ladanyi M. Am J Pathol 2000; 157: 341-345.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(2;11)(p23;p15). Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/t0211p23p15ID5213.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -610- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Comparative Cancer Cytogenetics

Nicole McNeil, Cristina Montagna, Michael J. Difilippantonio and Thomas Ried

Center for Cancer Research, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

August 2003

It has long been appreciated that tumor cells carry chromosomal aberrations (1). Deviation from the paired ordering of autosomes and sex chromosomes by either increasing or decreasing the copy number of a given chromosome, is referred to as aneuploidy. Errors in the faithful segregation of chromosomes during mitotic or meiotic cell division play a crucial role in the generation of chromosomal aneuploidies, the genetic consequences of which are increased copy numbers of oncogenes and loss of tumor suppressor genes. Cytogenetic abnormalities that affect the integrity of a chromosome are referred to as structural aberrations. These can be either balanced (i.e., no net gains or loss of DNA as in peri- or paracentric inversions and reciprocal translocations) or unbalanced translocations, including duplications, deletions, and non-reciprocal translocations (2). In particular, balanced chromosomal translocations are frequently observed and considered pathogenetic events in haematopoietic malignancies (2-6).

One outcome of a translocation is the re-positioning of an oncogene in proximity to a strong enhancer from another gene. This results in overexpression of the oncogene and can lead to cellular transformation. In human Burkitt's Lymphoma, mouse plasmacytomas and pro-B cell lymphomas, the c-myc oncogene is juxtaposed to the enhancer for the immunoglobulin heavy chain gene (1, 7, 8). Dysregulation of c-myc in this manner is believed to increase both the rate of cell division and chromosome instability (9). Balanced

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -611- chromosomal translocations can have oncogenic effects through the production of fusion proteins. For instance, in almost 95% of chronic myelogenous leukemia (CML) case a translocation between chromosomes 9 and 22 results in the formation of what is commonly referred to as the Philadelphia chromosome. This results in the fusion of the BCR and ABL genes. The BCR-ABL fusion protein has increased tyrosine kinase activity and transforms haematopoietic cells (10). Inhibition of the constitutive kinase activity with the BCR-ABL-specific inhibitor STI571 is currently in clinical trials and the overall response rate of patients in blast crisis in one study was reported to be 55%, with complete remission in 11% of the patients (11).

Karyotype analysis based on G- or R-banding techniques have been widely applied to the characterization of cytogenetic abnormalities in tumor cells and have contributed significantly to the identification of recurrently involved chromosomal loci and hence to the molecular cloning of cancer causing genes. In many instances, however, the cytogenetic analysis of chromosomes from solid tumors has proven to be challenging. This is due to the often-low mitotic index, the poor quality of metaphase chromosomes, and the sheer number of cytogenetic abnormalities (12). The use of genetically engineered mice as model systems of human cancer has fueled the need for better cytogenetic analysis in this species as well. Mouse chromosomes do not vary much in size and all are acrocentric. Therefore, some of the parameters used for identification of human chromosomes are less helpful, making karyotyping very difficult. A further drawback at present is that rather few cytogeneticists are trained in karyotyping mouse chromosomes.

The ability to microscopically visualize the location of individual sequences on metaphase chromosomes using fluorescence in situ hybridization (FISH) techniques has greatly broadened the application of cytogenetic methodologies, ushering in the era of molecular cytogenetics (for historical review (13)). FISH probes come in many varieties. They can be specific to (A) unique regions and genes, (B) repetitive sequences such as telomeres and centromeres, (C) entire chromosomes, chromosome bands or arms and (D) in the case of comparative genomic hybridization (CGH) as large as entire genomes. Advances in fluorochrome chemistry (i.e. stability, stoke shift, quantum yield, and conjugability to nucleotides) and photodetection devices (i.e., charged coupled device cameras and photomultiplier tubes) have further enhanced the sensitivity and multiplicity of FISH.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -612- The merging of these technical advances is reflected in the combinatorial labeling and hybridization techniques known as comparative genomic hybridization (CGH) (14), spectral karyotyping (SKY) (15, 16), and m-FISH (17, 18). CGH is a quantitative method for comparing the copy number of genomic regions between a control (DNA extracted from karyotypically normal cells) and test sample (i.e. tumor DNA). SKY and m-FISH involve the hybridization of differentially labeled chromosome painting probes for the identification of both numerical and structural aberrations in the genome. Each of these two conceptual methodologies alone provides a significant advance in the way we analyze genomes. Together, SKY, m-FISH and CGH offer novel tools to understand tumor specific and stage specific chromosome aberrations. In this chapter we provide some Deep Insights into the applications, uses, advantages and limitations of Spectral Karyotyping and Comparative Genomic Hybridization. We will also discuss how these two techniques are being applied to the classification, diagnosis, prognosis and understanding of the cellular mechanisms that lead to cellular transformation.

Spectral Karyotyping

Spectral karyotyping (SKY) is a molecular cytogenetic technique used to generate a color-coded karyotype of human and mouse chromosomes (15, 16). Prior to its development, cytogeneticists analyzed tumors and leukemias using a Giemsa staining technique that produced a dark and light banding pattern on chromosomes (Figure 1). As previously mentioned, chromosomal analysis using this technique alone can be challenging since tumor metaphase chromosomes are often poorly spread, have many rearrangements and subtle translocations or insertions. In combination with chromosome banding techniques, SKY allows for a more comprehensive description of cytogenetic abnormalities (Figure 2) (19).

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -613-

Figure1: Giemsa staining of chromosomes yields banding patterns.

(A) Human chromosomes come in pairs, one being maternal and the other paternal in origin. They are arranged on the basis of their size and the position of the centromere, or primary constriction. Most human chromosomes contain two arms. The p-arm is shorter and is oriented above the centromere while the q-arm is below the centromere. The normal complement of chromosomes in a human cell is 46. This karyotype is from a male cell as determined by the presence of both an X and Y chromosome. (B) Mouse chromosomes are also organized

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -614- according to their size, however all of the chromosomes are acrocentric (having the centromere close to one end and thus no p-arm), making karyotyping more of a challenge.

Figure 2 : Schematic representation of the steps involved in SKY analysis.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -615- (A) The process begins with the isolation of each individual chromosome by flow sorting. Each chromosome is then labeled with between 1 and 5 fluorochromes (combinatorial labeling) to create a unique spectral signature for each chromosome pair. Aliquots of the painted chromosomes are subsequently pooled together with an excess of Cot-1 DNA necessary to suppress the hybridization of labeled repetitive sequences common throughout the genome. (B) Both the SKY probe set and the chromosomes to be analyzed are heat denatured prior to hybridization for a 24-72 hour period at 37_C. (C) Unhybridized probe is removed by increasingly stringent washes. Detection of the non-fluorescently labeled probes is accomplished through the use of fluorescence-conjugated antibodies against the haptens biotin and digoxigenein. (D) The slide is illuminated with a Xenon lamp in order to simultaneously excite all of the fluorescent dyes. Thefluorescence emitted from the dyes then passes through a custom-designed triple bandpass optical filter to a Sagnac interferometer where an optical path difference is generated for each pixel. The emission spectra from each pixel is finally captured by a CCD camera and transmitted to the acquisition software. (E) Fourier transformation recovers the spectrum from this interferogram and assigns red, green, and blue (RGB) colors based on the wavelengths of the fluorescence intensities. (F) The result of the RGB assignment is the visualization of each chromosome as a unique spectral color. (G) Specialized analysis software then assigns an artificial classification color to each chromosome and places them into a karyotype. This is based on a classification table indicating which dye combinations were used for labeling of the chromosomes in Step A.

Spectral karyotyping involves the simultaneous hybridization of 24 chromosome-specific painting probes (Figure 2A). High-resolution, bi-variate flow sorting is first used to isolate each individual normal chromosome on the basis of its size, and A-T vs. G-C content (20). The source of the chromosomes are suspensions prepared from normal human or mouse cells, from cell lines with specific chromosomal rearrangements, human-hamster or mouse-hamster hybrid cell lines, and cell lines from different mouse strains. These combinations are necessary to assure the flow sorting of pure chromosomes. The DNA from each chromosome is then amplified by a degenerate oligo-primed polymerase chain reaction (DOP-PCR) (21). Next, each chromosome is labeled with either one or a combination of fluorochromes. Using such a

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -616- combinatorial labeling scheme with five different fluorochromes, 31 different targets can be distinguished. The combinatorial fluorescent labeling produces a unique spectral signature for each chromosome, thereby allowing the simultaneous discernment of all human or mouse chromosomes. After labeling, the chromosome painting probes are pooled together with an excess of Cot-1 DNA to suppress repetitive sequences within the genome and are hybridized onto metaphase chromosomes prepared from the sample of interest (i.e. tumor cells). Following incubation at 37 C for 24-72 hours, residual probe is removed by various stringency washes and subsequent detection steps allow visualization of fluorochromes. Note that only three direct fluorochromes are involved and that the biotin and digoxigenin labeled probes require detection with avidin conjugates or immunological detection (Figures 2B and 2C).

Spectral images are acquired using an interferometer connected to a CCD camera. The fluorochromes are excited by light emitted from a Xenon lamp passing through a custom-made triple-band pass optical filter. The light emitted from the sample (i.e. the fluorescence) is collected by the microscope objective and transferred to a Sagnac interferometer within the head of the Spectral Cube (Applied Spectral Imaging, Carlsbad, CA), which creates an optical path difference (16, 22) (Figure 2D). Fourier transformation resolves the resulting interferogram to a spectrum (Figure 2EF). Next, the spectral signature measured at each pixel is converted to a color code for visualization (Figure 2F). The classification colors are unique colors given to all chromosomes (pixels) that have the same spectrum (Figure 2G).

SKY has greatly enhanced the ability to analyze complex karyotypes from both human tumors and murine model systems. The wide application of SKY has clearly shown that, in combination with banding analyses, complex karyotypes can be resolved with unprecedented accuracy (for a reviews see (23, 24)).

Comparative Genomic Hybridization

Comparative Genomic Hybridization (CGH) employs two-color fluorescence in situ hybridization of both tumor DNA and normal control DNA (also known as reference DNA) to normal metaphase chromosomes (25). This molecular cytogenetic technique measures the genetic imbalances within tumor genomes, and has become an

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -617- exceedingly valuable tool for the analysis of chromosomal aberrations in solid tumors and haematological malignancies (26, 27). One major advantage of CGH is that only genomic tumor DNA is needed for analysis. Therefore, DNA extracted from archived, fixed tumors (28) as well as from microdissected tissue (29) can be analyzed.

After extraction of test DNA (i.e. from a tumor sample) and normal DNA (i.e. from peripheral blood), the samples are differentially labeled with discernable fluorochromes (i.e. tumor DNA with FITC [green] and control DNA with TRITC [red]) (Figure 3A). The two genomes are combined with an excess of human Cot-1 DNA and then hybridized to normal metaphase chromosomes (Figure 3B). Images of metaphase spreads are then acquired with a (charged coupled device) CCD camera and fluorochrome-specific optical filter sets to capture the FITC and TRITC fluorescence (Figure 3C). Differences in fluorescence intensity values between tumor and control DNA represent gains and losses of specific chromosomes or chromosomal regions (30). For example, a gain of a chromosomal region in the test sample would result in an increased intensity of green fluorescence. A loss within a chromosomal region in the tumor would be indicated by a shift towards red intensities. Specialized CGH analysis software measures fluorescence intensity values along the length of the chromosomes and translates the ratios into chromosome profiles (31). The ratio of green to red fluorescence values is used to quantitate genetic imbalances in tumor samples.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -618-

Figure 3 : Schematic representation of Comparative Genomic Hybridization.

(A) CGH begins with the isolation of both (1) genomic tumor DNA and (2) DNA from an individual with a normal karyotype (reference or control DNA). The two genomes are differentially labeled such that, for instance, the tumor DNA can be detected with a green fluorochrome (FITC) and the control DNA with a red fluorochrome (TRITC). (3) The differentially labeled genomes are then combined in the presence of excess Cot-1 DNA. (B) Both the probe and karyotypically normal target metaphase chromosomes are heat denatured prior to hybridization for a 24-72 hour period at 37ƒC. (C) Following a series of detection steps, metaphase chromosomes are imaged by epifluorescence microscopy with DAPI, FITC and TRITC filters consecutively. (1) The differences in fluorescence intensities along a chromosome are

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -619- a reflection of the actual copy number changes in the tumor genome relative to the normal reference. The result of the hybridization shows gains and losses; in the event that a specific chromosome region is lost in the tumor, the color of that region is shifted to red. A gain would be represented by an increased intensity of the green fluorescence. (2) A minimum of 5 metaphases (or 10 copies of each chromosome) are analyzed to determine an average ratio profile. A ratio of 1 represents an equal copy number in the tumor and the reference genome. The vertical lines to the left and right of the chromosome represent a loss (< 0.8) and a gain (>1.2), respectively.

Further modification of the CGH technique includes the replacement of metaphase chromosomes with unique DNA sequences spotted in arrays on a glass slide. Fluorescence intensities in both test and reference DNA hybridizations to the immobilized sequences on the array (i.e. cDNA, BAC or oligos) are averaged and normalized, and can be used to calculate an increase or decrease in copy number (32, 33). This array CGH allows for higher resolution of closely spaced genomic aberrations as well as the detection of microdeletions.

Comparative Cytogenetics

Cytogenetic analysis of human tumors reveals a non-random distribution of chromosome rearrangements resulting in genomic imbalances (34). Such aberrations are tissue specific and in some cases are fingerprints for a specific tumor. To better understand the significance of these chromosomal aberrations and identify in a controlled setting those that are early and disease initiating events, animal models of human cancer are extremely beneficial. The ability to generate gene-specific null mutants in mice affords us the opportunity to elucidate biochemical pathways leading to tumorigenesis and to query the relationship between chromosomal aberrations and the consequences of gene mutation on genomic stability. In addition, the generation of mouse strains hetero- or homozygously deficient for individual genes, the use of conditional knockouts, and inducible systems for transiently repressing or activating target genes increases the value of mouse models, particularly for cancer (35-38). Because the cytogenetic abnormalities observed in human cancers are fundamental, and often distinguishing features, it is extremely useful to evaluate whether the patterns of genomic imbalances are similar in human

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -620- tumors and their corresponding mouse models. The application of molecular cytogenetic techniques, such as SKY and CGH, has been a key factor in identifying similarities between human diseases and their respective mouse models. Mammary cancer is just one such example (39, 40).

The construction of human-mouse orthology maps and the sequencing of both genomes (41, 42) has greatly aided the process of comparative cytogenetics. For example, humans have 22 autosome pairs that vary greatly in size and most have two visible arms (p & q) separated by a centromere (Figure 1A). Mice, however, have 19 autosome pairs of relatively similar size with one arm and a centromere near the end (Figure 1B). Specific chromosomes or chromosome regions of one species can be mapped onto the chromosomes of different species, making it possible to follow chromosome reshuffling during evolution (Figure 4) (43). For instance, mouse chromosome 11 contains sequences orthologous to human chromosome 17, as well as regions of synteny with human 2p (red), 5q (gold), 7p (light pink), 16p (orange) and 22q (dark pink) (Fig 5). By following this comparative cytogenetic approach, we can evaluate chromosome gains and losses in similar tumor types from different species to determine if the same set of oncogenes or tumor suppressor genes is amplified or lost, respectively. Because genomic imbalances, generated primarily through chromosomal translocations or aneuploidies, are specific to each type of human malignancy, comparative analyses provides a validation of murine models and an entry point for the identification of new genes involved in tumorigenesis.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -621-

Figure 4 : Orthology map of human and mouse chromosomes.

(A) Each chromosome in the human ideogram is represented by a single unique color. (B) Every mouse chromosome (except the sex chromosomes) is comprised of regions from different human chromosomes. The regions of orthology can be identified by comparison of their color with the human ideogram in Panel A. Thus, during evolution mouse chromosome 1 has been redistributed to form portions of human chromosomes 8, 2 and 1.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -622-

Figure 5 : Synteny between mouse chromosome 11 (MMU11) and human chromosome 17(HSA17).

Mouse chromosome 11 contains portions of human chromosomes 22,7,2,16,5 and the entire chromosome 17.

Cytogenetic Analysis of Mouse Models of Haematopoietic Malignancies

Haematopoietic malignancies are quite distinct from solid tumors in that rather than gross chromosomal aneuploidy, the causative genomic alterations tend to result from the specific juxtaposition of genes or gene segments at the site of translocations. We have analyzed pro-B cell lymphomas, plasmacytomas and thymic lymphomas from a variety of different mouse models. In mice deficient for the gene mutated in ataxia telangiectasia (ATM) thymic lymphomas develop in nearly all of the animals between 2 and 4 months of age. These tumors exhibit a variety of chromosomal aberrations, including translocations, insertions, deletions, and duplications. Through the use of locus-specific BAC clones, we were able to determine that the breakpoint on chromosome 14 occurs at the T-cell receptor (Tcr)  locus during the programmed genomic recombination process known as V(D)J recombination (44). Other common aberrations included a deletion of the distal portion of chromosome 12 resulting in loss of the immunoglobulin heavy chain gene (IgH) as well as trisomy of chromosome 15, which contains the c-myc oncogene. Aberrations involving the T-cell receptor locus are also found in human ataxia

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -623- telangiectasia patients and support the use of the Atm mouse as a model for tumorigenesis in the absence of this gene product.

Mice deficient in Ku80, a protein involved in the non-homologous end joining (NHEJ) repair of DNA double strand breaks, also develop thymic lymphomas, but at a low frequency. These tumors almost invariably contain extra copies of chromosome 15 (45). When these, and mice deficient in other NHEJ proteins, are crossed onto a p53- deficient background, 100% of the mice now develop tumors, the spectrum of which shifts from T-cell to pro-B cell lymphoma (46-48). These tumors all harbor translocations involving chromosome 12 and 15 resulting in the juxtaposition and co-amplification of the IgH enhancer and the c-myc oncogene. While this rearrangement on the surface resembled that seen in human Burkitt's lymphoma, whereby the IgH enhancer and c-myc are also brought into close proximity, closer examination of the breakpoints in the mice revealed that the mechanism of translocation in these animals is quite distinct from that observed in the human disease and more closely reflects the type of aberrations (i.e. non-reciprocal translocations, gene amplification and complex chromosome rearrangements) often seen in the solid tumors (45, 49).

Another mouse model, which perhaps more closely mimics human Burkitt's lymphoma or multiple myeloma, is the induction of plasmacytomas in specific mouse strains (50, 51). In this system the rearrangements are believed to occur primarily in mature B-cells during the activation induced deaminase (AID)-dependent process of class switch recombination, not during V(D)J-mediated antigen receptor rearrangement in developing B-cells. The rearrangements involving the IgH locus on chromosome 12 and the c-myc locus on chromosome 15 are typically reciprocal in nature. However, in some instances amplification of the juxtaposed IgH & c-myc loci have been observed (52). Additionally, other differences are evident between this mouse model and the human diseases (53, 54).

Often in human haematopoietic malignancies, translocations result in the joining of two different genes and the production of fusion proteins. Mouse models have been developed in which the fusion protein is introduced as a transgene (for review see (55)). Such mice are extremely useful for studying the effects of expression of these chimeric molecules during the earliest stages of tumorigenesis. Identification of functional elements within the fusion proteins has been

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -624- achieved through the introduction of transgenes in which various regions have been modified. Thus, the use of mouse models for the study of human haematopoietic malignancies has proven to be extremely fruitful.

Cytogenetic Analysis of Mouse Models of Breast Cancer

Human breast carcinomas are defined by copy number increases frequently mapping to chromosomes 1q, 8q, 17q and 20q where a variety of oncogenes involved in breast cancer have been identified (56, 57). With this knowledge in hand, we applied SKY and CGH to the analysis of primary mammary tumors arising in knock-out mice of the tumor suppressor gene Brca1, mice transgenic for the oncogenes c-Myc or HER2/Neu, and mice expressing the polyoma virus middle T antigen or the SV40 large T antigen under control of the mammary gland tissue specific promoter MMTV (39, 40, 58). The distribution of gains and losses in each system revealed recurrent patterns of chromosomal aberrations, although each model was quite distinct. The Brca1 KO, however, contained aberrations more consistent with the rearrangements observed in human breast carcinomas.

The major imbalance observed in 58% of the HER2/Neu transgenic mouse tumors was deletion of chromosome 4 (MMU4) bands C-E. This suggested that in addition to HER2/Neu overexpression, decreased expression of a gene(s) in this region of chromosome 4 was important for the induction of mammary gland transformation (Figure 6). The distal portion of mouse chromosome 4 is orthologous to human 1p31-36 and 9p21, the latter of which contains the INK4 locus. In both the HER2/Neu and the C3(1)SV40Tag models, oncogene amplification results from the presence of acentric extra chromosomal fragments known as double minute chromosomes (dmin) (59, 60). Dmin play a critical role in tumor cell genetics where they are frequently associated with the overexpression of oncogene products (60-65). FISH using locus specific probes revealed that amplification of the HER2/Neu and K-Ras oncogenes was manifested as dmin in the HER2/Neu and C3(1)SV40Tag mouse models, respectively (Figure 7). This finding suggests that in addition to the presence of a strong initial stimulus for cellular transformation (i.e. the overexpression of an oncogene or the presence of a viral protein), secondary genetic alterations are necessary for tumor formation, at least in the mammary

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -625- gland. These results are consistent with the proposed step-wise increase in chromosome aberrations that parallels tumorigenic progression in human colorectal (66, 67) and cervical carcinomas (29, 56, 68-70).

Figure 6 : Chromosome gains and losses in the Her2/Neu transgenic mouse model.

CGH analysis reveals a deletion of chromosome four in the C-E band region as the major imbalance observed in this model. Either complete loss or reduced expression of a gene(s) present in this region of chromosome 4 may therefore be necessary for the induction of mammary gland transformation in the presence of Her2/Neu overexpression.

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -626-

Figure 7 : Double minute (dmin) chromosomes in metaphase and interphase cells from Her2/Neu and SV40 C3(1)/Tag transgenic mice.

(A) In the Her2/Neu transgenic mouse model, dmin chromosomes contain sequences of the Her2/Neu oncogene as demonstrated by hybridization of a locus specific BAC clone (yellow). In blue are shown the two copies of MMU11 (blue) containing the normal mapping position of the oncogene. (B) In the SV40 C3(1)/Tag mouse model, the K-ras oncogene (green) is amplified in the form of double minute chromosomes. The endogenous locus is on MMU6 (red).

A comparison of chromosomal alterations between mouse models and their human tumor counterparts enables further refinement of those regions necessary for tumorigenesis. For example, the region most commonly gained in mammary tumors is the distal portion of chromosome 11. This region is orthologous to an area of the human genome (17q25) amplified in human breast cancer as well as other types of epithelial tumors (34, 71). The tumor suppressor genes BRCA1 and Trp53, as well as the oncogenes HER2/Neu, Tbx2, Rad51c and Grb2 are located in MMU11C-E (72) and human 17q25. However, because the oncogenes in the mouse map closer to the centromere and are outside the region of amplification, we conclude that they are not responsible for tumorigenesis in the mouse, and therefore unlikely to be involved in human breast cancer development. Thus, another candidate gene(s) with oncogenic potential residing on human chromosome 17 may be important for mammary gland transformation.

Our results indicate that cytogenetic experiments conducted in mice with the use of comparative maps are an important tool for understanding the sequence of genetic events required for tumorigenesis. The results obtained can be used to better understand the processes involved in cellular transformation and for the

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -627- identification of molecular pathways conserved between mice and humans. Increasing the cytogenetic resolution is extremely useful not only for describing genetic alterations, but also for defining those genomic changes that are specific to each tumor type. This has largely been made possible through the combined application of CGH (for identifying regions of gain and loss) and SKY (to identify the mechanism by which the regional copy number or gene expression is altered). We believe that further sub-classification of tumors into more specific categories based on their genomic profile may prove useful in tailoring or identifying responsiveness to particular therapies.

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Contributor(s) Written 08- Nicole McNeil, Cristina Montagna, Michael J. Difilippantonio 2003 and Thomas Ri Citation This paper should be referenced as such : McNeil N, Montagna C, Difilippantonio MJ and Ried T . Comparative Cancer Cytogenetics. Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Deep/ComparCancerCytogID20011.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -636- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MLL: Deep Insight

Jay L. Hess M.D. Ph.D.

Department of Pathology, University of Michigan Medical School 5240 Medical Sciences Building 1, 1301 Catherine Road Ann Arbor, MI 48109-0602 E mail: [email protected]

January 2006

Introduction

The mixed lineage leukemia gene, MLL (also known as MLL1), is disrupted in a variety of aggressive human B and T lymphoid as well as myeloid leukemias [Hess, J. L., et al., 1997;Brock, H. W.and van Lohuizen, M., 2001] (Fig. 1, Table 1). MLL is homologous to Drosophila Trithorax, a positive regulator of transcription during development. The best understood target genes of MLL are the clustered homeobox or Hox genes, which are transcription factors that are involved in the specification of cell fate during development. MLL is widely expressed during development and is expressed in most adult tissues including myeloid and lymphoid cells and is required for definitive hematopoiesis [Hess, J. L., et al., 1997;Ernst, P., et al., 2001] . Previous studies showed that Mll (Mll = murine MLL) plays an important role in maintenance of Hox gene expression during development because heterozygous Mll knockout mice showed posterior shifts in Hox gene expression, and Mll knockout mice, which are embryonic, show loss of Hox gene expression after embryonic day 9.5 following normal initiation of expression [Yu, B. D., et al., 1995].

MLL structure

MLL (3968 aa) is rapidly proteolytically cleaved into two fragments before entering the nucleus [Nakamura, T., et al., 2002;Yokoyama, A., et al., 2002;Hsieh, J. J., et al., 2003a;Hsieh, J. J., et al., 2003b] (Fig. 1). The amino terminus of (MLLN) is a 320 kD protein that targets MLL to specific chromosomal sites (i.e. Hox genes). These sequences span the three N-terminal AT hooks, which have been shown to bind the minor groove of DNA. A second region with |40347| homology to DNA methyltransferases (DNMT1) and methyl CpG |41308||41668| binding proteins (MBD1/PCM1) termed RD1 contains a CXXC zinc finger domain that binds CpG rich DNA [Birke, M., et al., 2002]. Both the RD1 domain and a C terminal RD2 domain act as independent repressors of transcription [Xia, Z. B., et al., 2003]. MLL contains two

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -637- short domains SNL-1 and SNL-2 conserved with Drosophila trithorax (TRX) required for its punctate subnuclear localization [Yano, T., et al., 1997]. The C terminus of MLLN contains a region with high homology to trx. This region contains four cysteine- rich zinc finger domains (termed PHD for plant homeodomain) that flank a divergent bromodomain, a domain implicated in binding to acetylated histones [Aasland, R., et al., 1995](Fig. 1). This region of MLL homodimerizes and is non-covalently associated with the C terminal MLL fragment [Fair, K., et al., 2001;Nakamura, T., et al., 2002;Yokoyama, A., et al., 2002;Hsieh, J. J., et al., 2003a]. The PHD finger region also interact with Cyp33, which may result in transcriptional repression through enhancing binding of histone deacetylases HDAC 1 and 2 to the RD1 and RD2 domains [Xia, Z. B., et al., 2003].

MLL is cleaved C terminal to the PHD fingers at an evolutionarily conserved site by a novel endoprotease termed taspase [Hsieh, J. J., et al., 2003a] into a 180 kD fragment, (MLLC) with potent transcriptional activating activity [Yokoyama, A., et al., 2002]. In addition inhibition of cleavage by taspase knockdown results in inhibition of 3’ Hox expression [Hsieh, J. J., et al., 2003a]. Once cleaved the two halves of MLL remain non-covalently associated through an interaction between the FYRN domain of MLLN and the FYRC and SET domain of MLLC. Part of the transcriptional activation by MLLC appears to be the result of recruitment of the histone acetyltransferases CBP and MDF [Ernst, P., et al., 2001] resulting in acetylation of histones H3 and H4 at target genes. In addition the evolutionarily conserved SET domain has intrinsic histone methyltransferase activity specific for histone H3 lysine 4 [Milne, T. A., et al., 2002;Yokoyama, A., et al., 2002]. The SET methyltransferase preferentially methylates histone tails that are already acetylated. The MLL SET domain homodimerizes and also interacts with INI1, a core component of the SWI/SNF chromatin remodeling complex [Rozenblatt-Rosen, O., et al., 1998], which may also contribute to transcriptional activation. In addition to its multiple domains involved in transcriptional regulation MLL has been reported to associate with more than 30 different proteins including core components of the SWI/SNF chromatin remodeling complex (BAF170, BAF155, INI1) that are likely involved in transcriptional activation, including |42481| basal transcription factors (TBP, TAFII250, TAFII80, TAFII31, TAFII20), which may be involved in targeting MLL to promoters or else MLL delivers to promoters and two different histone deacetylase (HDAC) containing corepressor |40802||40803| complexes NuRD (Mi2, MTA1-L1, HDAC1, HDAC2, |41310||42298||42202||42201| RbAp46, RbAp48, MBD3, KIAA0601) and Sin3A (Sin3A, SAP30, SAP18, HDAC1, HDAC2, RbAp48, RbAp46 [Nakamura, T., et al., 2002]. The MLL complex reported is somewhat controversial in that the complex differs dramatically from other, more recently reported MLL complexes which include MLL complex members WDR5 and Rbpp5 as well as other mammalian homologs of the proteins in the yeast Set1 complex [Cui, X., et al., 1998;Ernst, P., et al., 2001;Petruk, S., et al., 2001]. Surprisingly this core complex also contains menin, the protein mutated in multiple endocrine neoplasia syndrome type I (MEN1), which was required for Hox gene activation [Hughes, C. M., et al., 2004]. Finally the PHD fingers of MLL interact with the cyclophilin Cyp33, an RNA binding protein that may modulate the recruitment of corepressors to the RD2 domains of MLLN [Fair, K., et al., 2001;Xia, Z. B., et al., 2003].

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -638- MLL regulates Hox transcription through direct promoter binding and histone modifications

MLL directly binds to Hox promoters such as Hox c8 and Hox a9 promoters and regulates their transcription through both acetylation of histones H3 and H4 at Hox promoter and enhancer sequences as well as histone H3 lysine 4 di- and trimethylation [Milne, T. A., et al., 2002;Nakamura, T., et al., 2002]. Because no known histone demethylases have been identified lysine methylation appears to be a long-term epigenetic mark for sustained transcription [Lachner, M.and Jenuwein, T., 2002]. The repressive PcG proteins are involved in Lys 9 and Lys 27 methylation strongly suggesting that histone methylation accounts for the antagonist effects of trx and PcG proteins on transcription [Cao, R., et al., 2002;Czermin, B., et al., 2002;Kuzmichev, A., et al., 2002;Muller, J., et al., 2002].

It is unclear whether H3 Lys 4 trimethylation is an absolute requirement for transcription and what the mediators are of this mechanism. Lys 4 methylation might block corepressor recruitment as it is for the histone deacetylase containing NuRD complex [Zegerman, P., et al., 2002]. A second possibility is that Lys4 di- or trimethylation creates a docking site for a transcriptional coactivator. The DNA dependent ATPase yeast protein ISW1p and its mammalian homolog hSNF2H, core components of the ISW1 chromatin remodeling complex preferentially bind to di- or trimethylated histone H3 lysine 4 [Santos-Rosa, H., et al., 2003]. ISW1p exists in two complexes, one of which ISW1b is required for promoting early stages of transcriptional elongation as well as termination by RNA polymerase II. In yeast both SET1, a lysine 4 methyltransferase homologous to MLL and Isw1p are required for full activation of target genes. Interestingly hSNF2 was also in the MLL complex [Nakamura, T., et al., 2002]. These findings suggest that MLL is intimately involved in a Lys 4 methylation and ATPase dependent mechanism to promote transcription [Krogan, N. J., et al., 2003]. Recent work indicates that MLL interacts with RNA polymerase II and acts to promote transcriptional elongation [Lachner, M.and Jenuwein, T., 2002].

MLL fusion proteins

Leukemogenic MLL rearrangements take a variety of forms including balanced translocations, partial tandem duplications of internal coding regions as well as amplification of apparently unrearranged forms of MLL (Fig. 1, Table 1). In rare cases of T-ALL exon 8 sequences are deleted resulting in disruption of the first PHD finger of MLL [Ayton, P. M.and Cleary, M. L., 2001]. However the most common MLL rearrangements are balanced translocations. The most frequent translocations in ALL are the t(4;11) and t(11;19) translocations, associated with expression of MLL-AF4 and MLL-ENL respectively, and pro-B cell or mixed lineage phenotype. Rarely MLL rearrangements such as MLL-ENL are seen in T-ALL. MLL translocations are also common in acute myelogenous leukemia, occurring in about 10% of cases. These leukemias are associated with a different set of translocations including the t(9;11) and t(6;11), which express MLL-AF9 and MLL-AF6 respectively. MLL rearrangements are also common in secondary acute leukemias arising following therapy with topoisomerase inhibitors such as etoposide [Felix, C. A., 1998].

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -639-

Fig. 1- MLL rearrangements associated with acute lymphoid and myeloid leukemias. MLL is homologous to Drosophila trithorax (trx) in a central PHD finger domain as well as in the C terminal SET domain (yellow). The AT hook and DNA methyltransferase homology regions are retained in all MLL rearrangements and are thought to mediate binding to specific chromosomal regions. Balanced translocations disrupt MLL in a breakpoint cluster region that spans exons 8 through 14 thereby deleting the sequences conserved with trx and replacing them with one of over 40 different translocation partners. Some such as MLL-AF4 and MLL-ENL are characteristically associated with ALL. Others such as AF6, AF9 and the majority of other translocations (X) are associated with AML, myelodysplasia or etoposide therapy related acute leukemia. In addition about 10% of AML cases without cytogenetic evidence of 11q23 rearrangements show internal tandem duplications of MLL, sometimes in association with trisomy 11.

AF4 AF4 (FEL) 4q21 Central transcriptional activation domain pro-B ALL related AF5q31Ý 5q31.1 Central transcriptional activation domain pro-B ALL LAF4Ý 2q11.2~q12 Central transcriptional activation domain Ýpro-B ALL AF9 AF9Ý 9p22 Central transcriptional activation domain AML related ENLÝ 19p13.3 Anc1 homology AML,

C-terminal transcriptional activationÝ domain pro-B ALL

Anc1 homology ELL ELL (MEN) 19p13.1 C-terminal transcriptional activation domain AML related RNA polymerase II elongation factor AF10 AF10Ý 10p12 N-terminal PHD finder domain, leucine zipper AML related SWI/SNF interaction, transcriptional activation AF17Ý 17q21 N-terminal PHD finder domain, leucine zipper AML CBP ÝCBP 16p13.3 Transcriptional activation, bromodomain AML related Histone acetyltransferase

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -640- P300Ý 22q13 Transcriptional activation, bromodomain AML

Histone acetyltransferase Forkhead AFXÝ Xq13 C-terminal transcriptional activation domain, T-ALL related forkhead DNA binding|1374| FKHR-L1Ý 6q21 C-terminal transcriptional activation domain, AML forkhead DNA binding domain

Table 1-Common MLL translocation partners occurring in leukemia Balanced translocations involving MLL cluster between exons 8 and 14 resulting in deletion of the PHD and distal domains and in frame fusion to one of many different translocation partners (Fig. 2). The fusion proteins apparently do not interact with MLLC [Yokoyama, A., et al., 2002]. Several lines of evidence suggest that MLL fusion proteins transform by a gain of function rather than loss of function mechanism. First growth of MLL null hematopoietic progenitors is impaired rather than enhanced [Hess, J. L., et al., 1997;Yagi, H., et al., 1998;Ernst, P., et al., 2001]. Heterozygous MLL knockout mice do not have an increased incidence of leukemia nor do knock-in mice in which murine Mll is truncated by a Myc epitope tag [Corral, J., et al., 1996]. However, if the murine Mll is fused in frame to AF9 so that an Mll-AF9 fusion protein is expressed all of the mice develop first an expansion of myeloid progenitors and ultimately acute myeloid leukemias after a several month latency period [Dobson, C. L., et al., 1999]. These studies suggest that transformation by MLL-AF9 (and presumably other MLL fusions) is mediated by gain of function and in addition that additional genetic “hits” are likely to be required for full transformation. Retroviral transduction of MLL fusion proteins such as MLL-ENL has shown similar findings [Lavau, C., et al., 1997]. Studies of conditional forms of MLL fusion proteins suggest this is mediated by imposition of a reversible block on myeloid differentiation [Martin, M. E., et al., 2003;Zeisig, B. B., et al., 2004]

Fig 2. Possible mechanisms of transcriptional activation by MLL fusion proteins. Wild type MLL is composed of a heterodimers of MLLN and MLLC. MLLN directs the MLL complex to specific chromosomal sites including a subset of Hox genes where the complex serves as a regulatable

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -641- activator of Hox genes. All MLL translocations result in loss of the conserved PHD fingers and SET domain and in frame fusion of MLL to one of more than 40 different translocation partners. The most common MLL fusion proteins involve nuclear translocation partners that act as potent transcriptional coactivators. Recent work suggests that some of the most common translocation partners, such as AF4 and AF9, interact and possibly recruit CDK9 and cyclin T1 to target promoters MLL [Zeisig, D. T., et al., 2005]. This potentially could promote transcriptional elongation through phosphorylation of RNA pol II 6 terminal domain by CDK9. Less commonly, MLL is fused to cytoplasmic translocation partners such as GAS7 and AF1p. These dimerize the truncated MLL molecule. This may involve recruitment of yet to be identified coactivators through MLLN sequences. This does not exclude the possibility that the translocation partner is also involved in coactivator recruitment. The domains in MLL fusion proteins required for transformation includes a serine threonine-rich sequence of unknown function at the extreme amino terminal of MLL as well as the DNMT homology region of MLL that is likely to be important for DNA binding [Slany, R. K., et al., 1998;Birke, M., et al., 2002;So, C. W., et al., 2003b]. The end result of these fusions is to convert the truncated MLL into a potent transcriptional activator [Schreiner, S. A., et al., 1999;Zeisig, B. B., et al., 2003]. In most cases this is the result of fusion of MLL to translocation partners that are strong transcriptional activators. For example, both ENL and AF9 are nuclear proteins that activate transcription when tethered to heterologous promoters. An 84 amino acid C terminal domain of ENL conserved with AF9 is all that is required for transformation. Recently ENL has been found to be present in an SWI/SNF like complex termed EBAF, which has nucleosomal remodeling activity [Nie, Z., et al., 2003]. The complex includes at least 8 proteins found in other SWI/SNF complexes including INI1 and the Brg1 DNA-dependent ATPase. The AF4 translocation partner is homologous to two other MLL translocation partners AF5q31 and LAF4, both of which are associated with pro-B cell leukemia. AF4 is also a potent activator of transcription when tethered to target promoters but less is known about its mechanism of activation in part because MLL-AF4 is unable to transform murine bone marrow in standard assays [Ayton, P. M.and Cleary, M. L., 2001]. AF4 and AF9 physically interact and colocalize at subnuclear foci suggesting that AF4 activation of transcription involves AF9 and SWI/SNF recruitment. The colocalization of AF4 and AF9 has prompted the “MLL Web hypothesis” that many MLL translocation partners are components of a larger supercomplex containing AF5q31, which itself interacts with CDK9 and cyclin T1 [Debernardi, S., et al., 2002;Erfurth, F., et al., 2004]. This is of potential significance because this complex phosphorylates the c terminal domain of RNA polymerase II and therefore may promote transcriptional elongation[Zeisig, D. T., et al., 2005]. MLL is fused to the known histone acetyltransferases CBP or p300 in some leukemias suggesting that abnormal histone acetyltransferase (HAT) activity may also play a role in MLL-mediated leukemogenesis. Structure function analysis of the MLL-CBP fusion protein shows that both the CBP HAT domain as well as an adjacent bromodomain are required for transformation [Lavau, C., et al., 2000]. Given that CBP also interacts with wild type MLL the question arises why when fused to MLL the protein becomes leukemogenic. One possibility is that deletion of potential negative regulatory sequences in CBP results in its abnormal activation. Alternatively covalent fusion may be important because this precludes regulated interactions with CBP that might be required for proper transcriptional regulation. CBP has also been implicated in transformation by other MLL fusion proteins. The MLL translocation partners AFX and FKHRL1 share two domains CR2 and CR3 that have been shown to cooperate in transcriptional activation and transformation [So, C. W.and Cleary, M. L., 2003]. The CR3 domain of interacts with CBP [So, C. W.and Cleary, M. L., 2002].

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -642- Like other forkhead transcription factors AFX induces cell cycle arrest and apoptosis by upregulating expression of p27Kip-1 [Medema, R. H., et al., 2000]. Interestingly MLL-AFX acts as a dominant negative inhibitor that suppresses FKHRL1 mediated apoptosis in myeloid cells suggesting that disruption of the normal activity of the translocation partner may play a role in the pathogenesis of the leukemia [So, C. W.and Cleary, M. L., 2002]. ELL is another translocation partner of MLL that was originally biochemically isolated as an elongation factor for RNA polymerase II [Shilatifard, A., et al., 1996]. The central R2 domain of ELL promotes elongation by suppressing polymerase pausing. However structure-function studies show that a carboxyl terminal R4 domain with transcriptional activating activity and not the R2 domain is necessary and sufficient for myeloid transformation [DiMartino, J., et al., 2000;Luo, R. T., et al., 2001]. This domain has transcriptional activating activity, possibly as a result of recruitment of an ELL associated protein EAF1, which contains a serine/aspartic acid/glutamic acid rich transactivation domain conserved with AF4, LAF4, and AF5q31 [Luo, R. T., et al., 2001]. EAF1 fused to MLL also is transforming in retroviral transformation assays suggesting EAF1 is the critical transcriptional activator required for transformation [Luo, R. T., et al., 2001]. Recent work suggests that menin is required for transformation by multiple MLL fusion proteins. The protein interacts with amino acid sequences in an evolutionarily conserved domain at the extreme amino terminus of MLL, which is shared by both MLL and MLL fusion proteins [Dobson, C. L., et al., 2000] . Deletion of this domain blocks transformation. In addition, genetic ablation of menin blocks transformation and reduces Hox gene expression thought to be pivotal for leukemogenesis. Despite similarities between some of the more common MLL translocations, many MLL translocation partners are not transcription factors. Some MLL translocation partners have self-association motifs, suggesting that dimerization of MLL is transforming. Further evidence for this is that fusion of MLL to Beta galactosidase, which is a tetramer in solution [Dobson, C. L., et al., 2000]. Subsequent experiments have conclusively shown that dimerization of MLL contributes to transformation by some MLL fusion proteins [Martin, M. E., et al., 2003;So, C. W., et al., 2003b] The mechanisms by which dimerization of MLL converts it into an oncogene are unknown. Dimerization converts truncated MLL into an extremely potent transcriptional transactivator that has increased binding affinity for Hox promoters and that increases the amount of wild type MLL at target loci [Milne, T. A., et al., 2005b] . Whether the wild type MLL is required for transformation is not known. The end result of dimerization of fusion proteins, however, is |40850||41331| upregulation of Hox a7, hox a9, and Meis1 expression to levels similar to those seen in leukemias with MLL fused to nuclear translocation partners [Martin, M. E., et al., 2003] (Fig. 3, Fig. 4).

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -643-

Fig 3. MLL and menin cooperatively regulate expression of Hox genes including Hoxa9 and Meis1. There are normally expressed on in early hematopoietic cells. During hematopoietic differentiation, both menin and MLL dissociate from target loci accompanied by a loss of histone modification, including histone H3 and H4 acetylation and H3 lysine 4 and lysine 79 methylation.

Fig 4. MLL fusion proteins potentially deregulate Hox gene expression through multiple mechanisms. The MLL fusion proteins increase the amount of wild type MLL at target loci [Milne, T. A., et al., 2005a]. Some MLL translocation partners such as AF5q31 interact with CDK9/cyclin T1 and therefore may influence transcriptional elongation via phosphorylation of the C-terminal domain of RNA polymerase II [Zeisig, D. T., et al., 2005 Lin, M. 2005]. Either directly or indirectly, MLL fusion proteins induce increased histone acetylation, lysine 4 methylation and, for some fusion proteins such as MLL-ENL, histone H3 lysine 79 methylation [Zeisig, D. T., et al., 2005].

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -644-

Partial tandem duplication of MLL

About 10% of AML with normal cytogenetics harbor internal tandem duplications of MLL (Fig. 1), an important finding because these cases are associated with a worse prognosis than those without MLL rearrangements [Schichman, S. A., et al., 1994]. Microarray studies on human leukemias with MLL PTD do not show the characteristic “signature” of Hox gene deregulation as leukemias with MLL translocations, leaving the mechanism of transformation unclear[Ross, M. E., et al., 2004].

MLL amplification

In some cases of MDS and AML MLL is present in increased copy number either as the result of additional copies of chromosome 11 or MLL amplification, either cytogenetically undetectable or in high copy number cases where MLL is present in homogeneous staining regions or double minute chromosomes [Thorsteinsdottir, U., et al., 2002;Poppe, B., et al., 2004]. The coding region of MLL is apparently unaltered but overexpressed in these cases. Amplification of MLL is also associated with upregulation of at least some of the genes consistently expressed in leukemias with MLL rearrangements including HOX A9, MEIS1, PROML1, ADAM10, NKG2D and ITPA expression, suggesting similar mechanisms of pathogenesis [Poppe, B., et al., 2004].

Hox genes are critical targets of leukemogenic forms of MLL

Hox genes appear to be the critical targets of MLL fusion proteins required for transformation. Hox genes such as Hox a9 are important regulators of hematopoiesis that act in part by promoting stem cell renewal [Sauvageau, G., et al., 2001;Thorsteinsdottir, U., et al., 2002]. The A cluster Hox genes including Hox a7 and a9 and the Hox cofactor Meis 1 are normally only expressed in early Sca1+Lin- hematopoietic stem cells and then their expression is rapidly downregulated [Pineault, N., et al., 2002] (Fig. 3). Studies of revealed that Hox a7 and Hox a9 are commonly overexpressed as a result of retroviral integration in leukemias spontaneously arising in BXH2 mice [Moskow, J. J., et al., 1995;Nakamura, T., et al., 1996]. Mice transplanted with murine bone marrow cells transduced with Hox a9 alone resulted in AML with a long latency of up to 6 months [Kroon, E., et al., 1998]. The Hox proteins bind to DNA as heterodimers and trimers with members of the TALE (three amino acid loop extension proteins) family members including PBX1, |41647||41648| PBX2, and PBX3 as well as Meis 1 [Schnabel, C. A., et al., 2000]. Notably overexpression of Meis 1 is commonly associated with Hox a7 and a9 expression in BXH2 leukemias, and cotransduction of Hox a9 and Meis 1 rapidly accelerates leukemia development in transplanted mice [Kroon, E., et al., 1998]. Human ALL with MLL rearrangements consistently express HOX A7, HOX A9 and MEIS1 in sharp contrast to morphologically and immunophenotypically similar leukemias that lack MLL rearrangements [Rozovskaia, T., et al., 2001;Armstrong, S. A., et al., 2002;Yeoh, E. J., et al., 2002;Ferrando, A. A., et al., 2003]. Recent experiments with a conditionally transforming version of MLL-ENL show that

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -645- expression of Hox a9 and Meis1 can replace the gain of function activity of the fusion proteins indicating these are critical MLL fusion protein targets [Zeisig, B. B., et al., 2004] and in addition retroviral transformation assays showing transformation by MLL-ENL requires functional Hox a7 and Hox a9 [Ayton, P. M.and Cleary, M. L., 2003]. Recently some questions have arisen regarding the role of Hox genes in MLL leukemogenesis. MLL-GAS7 was recently shown to transform Hox a9 knock-out bone marrow [So, C. W., et al., 2003a]. In addition Mll-AF9 knock-in mice develop leukemia with the same incidence and latency on either a Hox a9 null or wild type background [Kumar, A. R., et al., 2003]. One possible explanation is that MLL fusion proteins upregulate |40846| multiple other Hox genes including Hox a7, Hox a10 and Meis1 as well as non Hox targets such as Lmo2, N-Myc, and Flt3 [Kumar, A. R., et al., 2003] and that under certain conditions this is sufficient for transformation.

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Atlas Genet Cytogenet Oncol Haematol 2003; 4 -652- Borkhardt, A., Chanda, S. K., Walker, J., Soden, R., Hess, J. L. and Slany, R. K. Mol Cell Biol 2004; (24) 2:617-28. Medline 14701735 MLL associates specifically with a subset of transcriptionally active target genes. Milne, T. A., Dou, Y., Martin, M. E., Brock, H. W., Roeder, R. G. and Hess, J. L. Proceedings of the National Academy of Sciences of the United States of America 102(41):14765-70, 2005 Oct 11 2005a; Medline 16199523 Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Milne, T. A., Martin, M. E., Brock, H. W., Slany, R. K. and Hess, J. L. Cancer Research 65(24):11367-74, 2005 Dec 15 2005b; Medline 16357144 The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Zeisig, D. T., Bittner, C. B., Zeisig, B. B., Garcia-Cuellar, M. P., Hess, J. L. and Slany, R. K. Oncogene 2005; (24) 35:5525-32. Medline 15856011

Contributor(s) Written 08- Jay L. Hess 2003 Citation This paper should be referenced as such : Hess JL . MLL: Deep Insight. Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://AtlasGeneticsOncology.org/Deep/MLLdeepID20005.html

Atlas Genet Cytogenet Oncol Haematol 2003; 4 -653-