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t(3;12)(q26;p13) ETV6/MECOM

t(3;12)(q26;p13) ETV6/EVI1

Written1997-09François Desangles
Laboratoire de Biologie, Hopital du Val de Grace, 75230 Paris, France
Updated2014-04Etienne De Braekeleer, Nathalie Douet-Guilbert, Marc De Braekeleer
Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1008
Note Only a few cases were shown to involve a ETV6/MECOM fusion by FISH or RT-PCR. In other cases, only MECOM or ETV6 was shown to be rearranged by FISH. Over-expression of MECOM/EVI1 was found in other cases. Finally, no cytogenetic or molecular analysis was performed in a few cases.
 
  t(3;12)(q26;p13) G-banding - Courtesy Jean-Luc Lai and Alain Vanderhaegen.

Clinics and Pathology

Disease Myeloid lineage: MDS in transformation, AML, BC-CML
Phenotype / cell stem origin Multilineage involvement; MDS--> M0, M2, M4, M7.
Epidemiology 46 cases described so far; sex ratio: 29M/16F (1 unknown); age: 2.5-87 yrs (med: 49 yrs), unknown age for 10 cases.
Cytology Dysplasia of megakaryocytes, multilineage involvement.
 
Survival curve (21 patients, Mean: 12 mths, Median: 10 mths).
Prognosis See survival curve above.

Cytogenetics

Cytogenetics Molecular Heterogeneity of the EVI1 breakpoints, as evidenced by the Cytocell Aquarius EVI1 Breakapart probe. The EVI1 Breakapart probe contains three probes: a probe labeled in Aqua of 562 kb in size centromeric to the EVI1 gene, a probe labeled in Spectrum Green of 181 kb covering EVI1 and its flanking regions and a probe labeled in Spectrum Orange of 124 kb telomeric of the EVI1 gene (telomeric of MYNN and covering LRRC34).
Additional anomalies Sole anomaly in 22 cases. Additional anomalies: t(9;22)(q34;q11) in 5 cases, -7/del(7q) in 11 cases, del(5q) in 2 cases, others in 6 cases.

Genes involved and Proteins

Gene NameMECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1-EVI1)
Location 3q26.2
Note Alias EVI1
Dna / Rna MECOM is a "complex entity" made of two genes, EVI1 and MDS1. EVI1 has 16 exons, of which 14 are coding, the start ATG codons being in exon 3. MDS1 has 4 exons, exon 4 being located in the vicinity of exon 1 of EVI1. Splicing of the second exon of MDS1 to the second exon of EVI1 leads to a MDS1-EVI1 mRNA.
Protein EVI1 contains two domains of seven and three zinc finger motifs separated by a repression domain and an acidic domain at its C-terminus.
Gene NameETV6 (ets variant 6)
Location 12p13.2
Note The ETV6 gene encodes a transcription factor frequently rearranged in myeloid and lymphoid leukemias.
Dna / Rna The ETV6 gene spans a region of less than 250 kb at band 12p13.1 and consists of 8 exons. There are two start codons, one (exon 1a starting at codon 1) located at the beginning of the gene and another alternative (exon 1b starting at codon 43) upstream of exon 3.
Protein The ETV6 protein (452 amino acids) contains two major domains, the HLH (helix-loop-helix) and ETS domains. The HLH domain, also referred to as the pointed or sterile alpha motif domain, is encoded by exons 3 and 4 and functions as a homo-oligodimerization domain. The ETS domain, encoded by exons 6 through 8, is responsible for sequence specific DNA-binding and protein-protein interaction.

Result of the chromosomal anomaly

Hybrid gene
Description Two mechanisms for generating the fusion gene, depending upon the involvement of the MDS1 gene.
Transcript 1) In-frame transcript consisting of the first two exons of ETV6 fused to MDS1 sequences, which in turn is fused to the second exon of the EVI1 gene.
2) Out-of-frame fusion by direct fusion between exon 2 of ETV6 and exon 2 of EVI1, but keeping the open reading frame of EVI1 intact.
  
Fusion Protein
 
  Schematic diagram of the ETV6, EVI1, MDS1, MDS1-EVI1, ETV6-EVI1 and ETV6-MDS1-EVI1 proteins.
Description ETV6 contributes no known functional domain to the predicted chimeric protein but functional domains of EVI1 are retained.
Oncogenesis The oncogenic potential of the translocation could be the result of the ETV6 promoter driving the transcription of EVI1. Because the ETV6 promoter is active in hematopoietic cells, this would result in inappropriate expression of the transcription factor EVI1.
  

Bibliography

An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies.
Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML.
Br J Haematol. 2007 Mar;136(6):806-13.
PMID 17341266
 
Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family.
Fears S, Mathieu C, Zeleznik-Le N, Huang S, Rowley JD, Nucifora G.
Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1642-7.
PMID 8643684
 
Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation.
Golub TR, Barker GF, Lovett M, Gilliland DG.
Cell. 1994 Apr 22;77(2):307-16.
PMID 8168137
 
ETV6 rearrangements are recurrent in myeloid malignancies and are frequently associated with other genetic events.
Haferlach C, Bacher U, Schnittger S, Alpermann T, Zenger M, Kern W, Haferlach T.
Genes Chromosomes Cancer. 2012 Apr;51(4):328-37. doi: 10.1002/gcc.21918. Epub 2011 Dec 8.
PMID 22162288
 
Expression of the TEL/EVI1 fusion transcript in a patient with chronic myelogenous leukemia with t(3;12)(q26;p13).
Nakamura Y, Nakazato H, Sato Y, Furusawa S, Mitani K.
Am J Hematol. 2002 Jan;69(1):80-2.
PMID 11835339
 
The EVI1 gene in myeloid leukemia.
Nucifora G.
Leukemia. 1997 Dec;11(12):2022-31. (REVIEW)
PMID 9447815
 
Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors.
Paquette RL, Nicoll J, Chalukya M, Elashoff D, Shah NP, Sawyers C, Spiteri E, Nanjangud G, Rao PN.
Cancer Genet. 2011 Jul;204(7):392-7. doi: 10.1016/j.cancergen.2011.06.002.
PMID 21872826
 
Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders.
Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P.
Cancer Res. 1997 Feb 15;57(4):564-9.
PMID 9044825
 
EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements.
Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F.
Genes Chromosomes Cancer. 2006 Apr;45(4):349-56.
PMID 16342172
 
Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes.
Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, Dyer M, Fuzibet JG, Gratecos N, Taillan B, Ayraud N, Marynen P.
Blood. 1996 Jul 15;88(2):682-9.
PMID 8695816
 
Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study.
Secker-Walker LM, Mehta A, Bain B.
Br J Haematol. 1995 Oct;91(2):490-501.
PMID 8547101
 
The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator.
Soderholm J, Kobayashi H, Mathieu C, Rowley JD, Nucifora G.
Leukemia. 1997 Mar;11(3):352-8.
PMID 9067573
 
Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: case report and review of the literature.
Voutsadakis IA, Maillard N.
Am J Hematol. 2003 Feb;72(2):135-7. (REVIEW)
PMID 12555218
 
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions.
Wieser R.
Gene. 2007 Jul 15;396(2):346-57. Epub 2007 Apr 20.
PMID 17507183
 
Breakpoint analysis by fluorescence in situ hybridization in myelodysplastic syndromes with t(3;12)(q26;p13) and expression of EVI1.
van de Loosdrecht AA, Kok K, de Vries B, van der Veen AY, van den Berg E, Esselink MT, Marynen P, Vellenga E, van Imhoff GW.
Leukemia. 2000 Oct;14(10):1857-8.
PMID 11021761
 

Citation

This paper should be referenced as such :
Braekeleer E De, N Douet-Guilbert, Braekeleer M De
t(3;12)(q26;p13) ETV6/MECOM - t(3;12)(q26;p13) ETV6/EVI1
Atlas Genet Cytogenet Oncol Haematol. 2014;18(12):950-953.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0312ID1008.html
History of this paper:
Desangles, F. t(3;12)(q26;p13). Atlas Genet Cytogenet Oncol Haematol. 1997;1(1):22-22.
http://documents.irevues.inist.fr/bitstream/handle/2042/32033/09-1997-t0312ID1008.pdf


Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes ETV6 MECOM

Translocations implicated (Data extracted from papers in the Atlas)

 t(3;12)(q26;p13) ETV6/MECOM

External links

ETV6 (12p13.2) MECOM (3q26.2)

ETV6 (12p13.2) MECOM (3q26.2)

Mitelman databaset(3;12)(q26;p13) [Case List]    t(3;12)(q26;p13) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9975/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9989/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseETV6/MECOM [MCList]  ETV6 (12p13.2) MECOM (3q26.2)
TICdbETV6/MECOM  ETV6 (12p13.2) MECOM (3q26.2)
 
Disease databaset(3;12)(q26;p13) ETV6/MECOM
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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