Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13)

We identified a novel human long fatty acyl CoA synthetase 2 gene, ACS2, as a new ETV6 fusion partner gene in a recurrent t(5;12)(q31;p13) translocation 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). ACS2 is expressed in the brain and bone marrow and is highly conserved in man and rats. The resulting ETV6/ACS2 fusion transcripts showed an out‐frame fusion of exon 1 of ETV6 to exon 1 of ACS2 in the AEL case, an out‐frame fusion of exon 1 of ETV6 to exon 11 of ACS2 in the AML case, and a short in‐frame fusion of ETV6 exon 1 to the 3′ untranslated region of ACS2 in the RAEB case. Reciprocal ACS2/ETV6 transcripts were identified in two of the cases. Fluorescence in situ hybridization (FISH) analysis with ETV6 cosmids on 12p13, and BACs and P1s on 5q31, demonstrated that the 5q31 breakpoints of the AML and AEL cases involved the 5′ portion of the ACS2 gene, and that the 5q31, breakpoint of the RAEB case involved the 3′ portion of the ACS2 gene. None of the resulting chimeric transcripts except for the ACS2/ETV6 transcript in the RAEB case led to a fusion protein. Disruption of the second ETV6 allele by t(12;19) was detected in the AML case by FISH analysis. These observations suggest that the disruption of ETV6 and/or ACS2 may lead to the pathogenesis of hematologic malignancies with t(5;12)(q31;p13). Genes Chromosomes Cancer 26:192–202, 1999. © 1999 Wiley‐Liss, Inc.

[1]  M. Frohman.  [42] – Rapid Amplification of Complementary DNA Ends for Generation of Full-Length Complementary DNAs: Thermal RACE , 1995 .

[2]  V. Buckle,et al.  Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q- syndrome: delineation of the critical region on 5q and identification of a 5q- breakpoint. , 1994, Genomics.

[3]  R. Espinosa,et al.  Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[4]  P. Riegman,et al.  Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. , 1995, Oncogene.

[5]  M. Daly,et al.  Familial eosinophilia maps to the cytokine gene cluster on human chromosomal region 5q31-q33. , 1998, American journal of human genetics.

[6]  N. Zhao,et al.  Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and preparation of a PAC-based physical map. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Marynen,et al.  Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. , 1996, Blood.

[8]  L. Wiedemann,et al.  The novel activation of ABL by fusion to an ets-related gene, TEL. , 1995, Cancer research.

[9]  J. Rothman,et al.  Possible role for fatty acyl-coenzyme A in intracellular protein transport , 1987, Nature.

[10]  R. Vale,et al.  RNA on the move: the mRNA localization pathway [published erratum appears in J Cell Biol 1993 Dec;123(6 Pt 1):1625] , 1993, The Journal of cell biology.

[11]  Iscn.  International System for Human Cytogenetic Nomenclature , 1978 .

[12]  P. Marynen,et al.  Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. , 1998, Blood.

[13]  P. Marynen,et al.  Genomic organization of TEL: the human ETS-variant gene 6. , 1996, Genome research.

[14]  N. Lenny,et al.  AML-2 is a potential target for transcriptional regulation by the t(8;21) and t(12;21) fusion proteins in acute leukemia. , 1996, Oncogene.

[15]  K. Ohyashiki,et al.  Late appearance of t(5;12)(q31;p12) in acute myeloid leukemia associated with eosinophilia. , 1998, Cancer genetics and cytogenetics.

[16]  E. Macintyre,et al.  High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. , 1995, Blood.

[17]  R. Kucherlapati,et al.  Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases. , 1994, Blood.

[18]  J. Warrington,et al.  Consistent loss of the D5S89 locus mapping telomeric to the interleukin gene cluster and centromeric to EGR-1 in patients with 5q- chromosome. , 1994, Blood.

[19]  P. Marynen,et al.  Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. , 1997, Blood.

[20]  Tokuo T. Yamamoto,et al.  Cloning and functional expression of a novel long-chain acyl-CoA synthetase expressed in brain. , 1992, Journal of biochemistry.

[21]  Todd R. Golub,et al.  Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation , 1994, Cell.

[22]  J. Boultwood,et al.  The 5q-syndrome. , 1994, Blood.

[23]  P. Marynen,et al.  Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. , 1997, Cancer research.

[24]  R. Grand,et al.  Acylation of viral and eukaryotic proteins. , 1989, The Biochemical journal.

[25]  K. Frazer,et al.  Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region. , 1997, Genome research.

[26]  P. Bentley,et al.  Potentiation of diacylglycerol-activated protein kinase C by acyl-coenzyme A thioesters of hypolipidaemic drugs. , 1989, Biochemical and biophysical research communications.

[27]  M. Frohman,et al.  Rapid amplification of complementary DNA ends for generation of full-length complementary DNAs: thermal RACE. , 1993, Methods in enzymology.

[28]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[29]  W. Pardridge,et al.  Ten nucleotide cis element in the 3'-untranslated region of the GLUT1 glucose transporter mRNA increases gene expression via mRNA stabilization. , 1998, Brain research. Molecular brain research.

[30]  D C Ward,et al.  Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A. Inoue,et al.  Fatty acyl-CoAs are potent inhibitors of the nuclear thyroid hormone receptor in vitro. , 1990, Journal of biochemistry.

[32]  D. Ledbetter,et al.  Rapid isolation of DNA probes within specific chromosome regions by interspersed repetitive sequence polymerase chain reaction. , 1990, Genomics.

[33]  H. Liang,et al.  Translocations and deletions of 5q13.1 in myelodysplasia and acute myelogenous leukemia: evidence for a novel critical locus. , 1996, Blood.

[34]  H. Murakami,et al.  Myelodysplastic syndrome with bone marrow eosinophilia: clinical and cytogenetic features. , 1994, Leukemia & lymphoma.

[35]  J. Rowley,et al.  A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B‐cell ALL cell line , 1997 .