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

• Published in: Genes chromosomes & cancer 2005-03, Vol.42 (3), p.269-279
• Main Authors: Hosoya, Noriko, Qiao, Ying, Hangaishi, Akira, Wang, Lili, Nannya, Yasuhito, Sanada, Masashi, Kurokawa, Mineo, Chiba, Shigeru, Hirai, Hisamaru, Ogawa, Seishi
• Format: Article
• Language: English
• Subjects: Aged; Animals; Chromosomes, Human, Pair 12 - genetics; Chromosomes, Human, Pair 6 - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; ETS Translocation Variant 6 Protein; Female; Genes, Dominant; Histones - metabolism; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute - genetics; Mice; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NIH 3T3 Cells; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - chemistry; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Phosphorylation; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-ets; Recombinant Fusion Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription, Genetic; Translocation, Genetic
• ISSN: 1045-2257; 1098-2264
• DOI: 10.1002/gcc.20147

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. © 2004 Wiley‐Liss, Inc.