Identification of a SRC-like tyrosine kinase gene, FRK, fused with ETV6 in a patient with acute myelogenous leukemia carrying a t(6;12)(q21;p13) translocation.
The SRC family of kinases is rarely mutated in primary human tumors. We report the identification of a SRC-like tyrosine kinase gene, FRK (Fyn-related kinase), fused with ETV6 in a patient with acute myelogenous leukemia carrying t(6;12)(q21;p13). Both reciprocal fusion transcripts, ETV6/FRK and FRK/ETV6, were expressed. In ETV6/FRK, exon 4 of ETV6 was fused in-frame to exon 3 of FRK, producing a chimeric protein consisting of the entire oligomerization domain of ETV6 and the kinase domain of FRK. The ETV6/FRK protein was shown to be constitutively autophosphorylated on its tyrosine residues. ETV6/FRK phosphorylated histones H2B and H4 in vitro to a greater extent than did FRK, suggesting it had elevated kinase activity. ETV6/FRK could transform both Ba/F3 cells and NIH3T3 cells, which depended on its kinase activity. Moreover, ETV6/FRK inhibited ETV6-mediated transcriptional repression in a dominant-negative manner. This report provides the first evidence that a SRC-like kinase gene, FRK fused with ETV6, could directly contribute to leukemogenesis by producing an oncoprotein, ETV6/FRK, with dual functions: constitutive activation of the ETV6/FRK tyrosine kinase and dominant-negative modulation of ETV6-mediated transcriptional repression.
Hosoya
Noriko
N
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Qiao
Ying
Y
Hangaishi
Akira
A
Wang
Lili
L
Nannya
Yasuhito
Y
Sanada
Masashi
M
Kurokawa
Mineo
M
Chiba
Shigeru
S
Hirai
Hisamaru
H
Ogawa
Seishi
S
D000368:Aged; D000818:Animals; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D006657:Histones / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D006657:Histones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C092830:FRK protein, human