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t(5;12)(q31;p13) ETV6/ACSL6 in MDS,AML and AEL

Written2007-03Maria D. Odero
Departamento de Genetica, Facultades de Ciencias y Medicina, y Area de Oncologia, Centro de Investigacion Medica Aplicada (CIMA), Universidad de Navarra, 31008-Pamplona, Espana

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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 1344
 
  t(5;12)(q31;p13) G- banding - left: Courtesy Melanie Zenger and Claudia Haferlach; middle and right: Courtesy Diane H Norback, Eric B Johnson, and Sara Morrison-Delap,UW Cytogenetic Services.

Clinics and Pathology

Disease The t(5;12)(q31;p13) translocation involving ETV6 (12p13) and ACSL6 (5q31) was found in a patient with refractory anemia with excess blasts (RAEB) with basophilia, a patient with acute myelogenous leukemia (AML) with eosinophilia, and a patient with acute eosinophilic leukemia (AEL).
Phenotype / cell stem origin Myeloid lineage
Epidemiology To date, one case with myelodysplastic syndrome (RAEB), one case with AML, one case with AEL, one case with atypical CML, and 2 cases with Polycythemia Vera (PV).
The t(5;12)(q31;p13) is a recurrent translocation in myeloid malignancies (at least 23 cases reported).
Prognosis No prognostic value established.

Cytogenetics

Cytogenetics Morphological May be not easy to detect.
Cytogenetics Molecular The translocation can be detected by FISH with ETV6 probes. The ETV6 gene is rearranged, and the breakpoint is between exon 1 and exon 2 in all cases reported.
Additional anomalies Disruption of the second ETV6 allele by t(12;19) was detected in the AML case by FISH analysis.
Variants No variants

Genes involved and Proteins

Gene NameETV6 (ets variant 6)
Location 12p13.2
Note The gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma .
Dna / Rna 9 exons; alternate splicing
Protein The gene encodes an ETS family transcription factor; the product of this gene contains a N-terminal pointed (PNT) domain that is involved in the protein-protein interactions, and a C-terminal ETS DNA-binding domain; wide expression; nuclear localization.
Gene NameACSL6 (acyl-CoA synthetase long-chain family member 6)
Location 5q31.1
Note None of the resulting chimeric transcripts, except for the ACSL6/ETV6 transcript in the RAEB case, led to a fusion protein.
Dna / Rna 57,74 kb, 21 exons; alternate splicing
Protein Two splicing isoforms, a long and a short. The gene encodes an AMP binding enzyme; plays an important role in fatty acid metabolism in brain, responsible for activation of long-chain fatty acids in erythrocytes. Wide expression, expression low at earlier stages of erythroid development but very high in reticulocytes.

Result of the chromosomal anomaly

Hybrid gene
Description A novel human gene, called ACS2 (acyl-CoA synthetase-2), was identified as an ETV6 fusion partner in a recurrent t(5;12)(q31;p13) translocation. Northern blot analysis detected high levels of ACS2 expression in brain, fetal liver, and bone marrow, and the gene was found to be highly conserved in man and rat. The ETV6/ACSL6 fusion transcripts showed an out-frame fusion of exon 1 of ETV6 to exon 1 of ACSL6 in the AEL patient, an out-frame fusion of exon 1 of ETV6 to exon 11 of ACSL6 in the AML patient, and a short in-frame fusion of exon 1 of ETV6 to the 3-prime untranslated region of ACSL6 in the patient with RAEB. Reciprocal ACSL6/ETV6 transcripts were identified in 2 of the cases. FISH with ETV6 cosmids on 12p13, and BACs and PIs on 5q31, demonstrated that the 5q31 breakpoints of the AML and AEL cases involved the 5-prime portion of the ACSL6 gene, and that the 5q31 breakpoint of the RAEB case involved the 3-prime portion of the ACSL6 gene. None of the resulting chimeric transcripts except for the ACSL6/ETV6 transcript in the RAEB case led to a fusion protein.
A case with a CML and a t(5;12)(q31;p13) was characterized, and 3 different ETV6/ACSL6 transcripts were detected. Moreover, as a consequence of the translocation IL-3/CSF2, located at 5q31, was ectopically expressed in the leukemic cells.
  

Bibliography

Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13).
Cools J, Mentens N, Odero MD, Peeters P, Wlodarska I, Delforge M, Hagemeijer A, Marynen P
Blood. 2002 ; 99 (5) : 1776-1784.
PMID 11861295
 
t(5;12)(q23-31;p13) with ETV6-ACSL6 gene fusion in polycythemia vera.
Murati A, Adélaïde J, Gelsi-Boyer V, Etienne A, Rémy V, Fezoui H, Sainty D, Xerri L, Vey N, Olschwang S, Birnbaum D, Chaffanet M, Mozziconacci MJ
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2006 ; 20 (6) : 1175-1178.
PMID 16572202
 
Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13).
Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K
Genes, chromosomes & cancer. 1999 ; 26 (3) : 192-202.
PMID 10502316
 

Citation

This paper should be referenced as such :
Odero, MD
t(5;12)(q31;p13) in MDS, AML, AEL
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):247-248.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0512q31p13ID1344.html


Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes ETV6

Translocations implicated (Data extracted from papers in the Atlas)

 t(5;12)(q31;p13) ETV6/ACSL6 in MDS,AML and AEL

External links

ETV6 (12p13.2) ACSL6 (5q31.1)

ETV6 (12p13.2) ACSL6 (5q31.1)

Mitelman databaset(5;12)(q31;p13) [Case List]    t(5;12)(q31;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/ACSL6 [MCList]  ETV6 (12p13.2) ACSL6 (5q31.1)
TICdbETV6/ACSL6  ETV6 (12p13.2) ACSL6 (5q31.1)
 
Disease databaset(5;12)(q31;p13) ETV6/ACSL6 in MDS,AML and AEL
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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