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t(9;12)(q34;p13) ETV6/ABL1

Written2000-12Nyla A Heerema
The Ohio State University, Division of Clinical Pathology, Department of Pathology, 167 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA
Updated2014-03Etienne 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 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
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 1080

Clinics and Pathology

Disease Malignant hemopathies (26 cases reported)
Phenotype / cell stem origin AML (3 cases), B-cell ALL (8 cases), T-cell ALL (1 case), RAEB evolving into AML (1 case), chronic myeloproliferative neoplasm (2 cases), Philadelphia chromosome-negative CML (11 cases).
Epidemiology Gender: 17 males, 8 females; age at diagnosis: 8 months to 81 years.
Clinics Eosinophilia appears to be a common feature of malignancies associated with the ETV6-ABL1 fusion gene (15/20 cases).

Genetics

The t(9;12)(q34;p13) involves the ETV6 gene (12p13), a transcription factor frequently rearranged in myeloid and lymphoid leukemias. More than 30 ETV6 fusion gene partners have been described. Most translocations involving ETV6 generate fusion genes that lead to the activation of transcription factors or kinases but other mechanisms are also known (loss of function of the fusion gene affecting ETV6 and the partner gene, activation of a proto-oncogene in the vicinity of a chromosomal translocation and dominant negative effect of the fusion protein over transcriptional repression mediated by wild-type ETV6).

Cytogenetics

Note t(9;12)(q34;p13) as the sole abnormality or associated with other abnormalities.
Cytogenetics Morphological t(9;12)(q34;p13) is very difficult to be identified by conventional cytogenetics.
Cytogenetics Molecular t(9;12)(q34;p13) usually requires FISH analysis with ETV6 and ABL1 probes to be detected (cryptic translocation). Insertions are also frequently identified.
Additional anomalies Additional anomalies are frequent but show no consistent features (trisomies and monosomies of various chromosomes, structural rearrangements including deletions and translocations).
Variants t(9;12;14)(q34;p13;q22) (seen in conventional cytogenetics),
t(8;9;12)(p12;q34;p13) (seen in conventional cytogenetics),
ins(9;12)(q34;p13p13) (seen by molecular cytogenetics),
ins(12;9)(p13;q34q34) (seen by molecular cytogenetics).

Genes involved and Proteins

Note As both genes have opposite orientation in relation to the centromeres, an in frame ETV6-ABL1 fusion gene requires at least three chromosomal breaks to be generated.
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.
Gene NameABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location 9q34.12
Dna / Rna The ABL1 gene, spanning a 230-kb region at band 9q34, includes the 5' alternative first exons 1b and 1a and ten common exons numbered from 2 to 11. Alternative splicing using exons 1b and 1a gives rise to mRNA of 7 and 6 kb, respectively.
Protein The ABL1 protein has three SRC homology (SH) domains called SH1, SH2 and SH3, of which SH1 that has a tyrosine kinase function. The SH2 and SH3 domains are involved in protein-protein interactions, which regulate the tyrosine kinase activity; they are necessary for signal transduction function. The ABL1 protein has also three nuclear localization signal domains and three DNA binding regions and an F-actin binding domain.

Result of the chromosomal anomaly

Hybrid gene
Transcript Two ETV6-ABL1 transcripts were identified in most of the patients, one joining exon 5 of ETV6 to exon 2 of ABL1, the other, usually found at very low levels, joining ETV6 exon 4 to ABL1 exon 2.
  
Fusion Protein
 
  Schematic diagram of the ETV6, ABL1 and ETV6-ABL1 proteins.
Description The fusion protein retains all three SH domains, including the tyrosine kinase domain, of ABL1, which make these patients sensitive to tyrosine kinase inhibitors. The retained N-terminal part of the ETV6 protein contains the helix-loop-helix domain necessary for oligomerization of the protein, which is required for tyrosine kinase activation, cytoskeletal localization and neoplastic transformation.
Oncogenesis Constitutive tyrosine kinase activation of ABL1.
  

Bibliography

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Establishment and cytogenetic characterization of a human acute lymphoblastic leukemia cell line (ALL-VG) with ETV6/ABL1 rearrangement.
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Citation

This paper should be referenced as such :
Braekeleer E De, N Douet-Guilbert, Braekeleer M De
t(9;12)(q34;p13) ETV6/ABL1
Atlas Genet Cytogenet Oncol Haematol. 2014;18(11):859-861.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t912ID1080.html
History of this paper:
Heerema, NA. t(9;12)(q34;p13). Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):42-43.
http://documents.irevues.inist.fr/bitstream/handle/2042/37705/12-2000-t912ID1080.pdf


Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

Genes ABL1 ETV6 GAB2

Translocations implicated (Data extracted from papers in the Atlas)

 t(9;12)(q34;p13) ETV6/ABL1

External links

ETV6 (12p13.2) ABL1 (9q34.12)

ETV6 (12p13.2) ABL1 (9q34.12)

Mitelman databaset(9;12)(q34;p13) [Case List]    t(9;12)(q34;p13) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9837/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
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/ABL1 [MCList]  ETV6 (12p13.2) ABL1 (9q34.12)
TICdbETV6/ABL1  ETV6 (12p13.2) ABL1 (9q34.12)
 
Disease databaset(9;12)(q34;p13) ETV6/ABL1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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