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

✍ Scribed by Noriko Hosoya; Ying Qiao; Akira Hangaishi; Lili Wang; Yasuhito Nannya; Masashi Sanada; Mineo Kurokawa; Shigeru Chiba; Hisamaru Hirai; Seishi Ogawa

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 637 KB
• Volume: 42
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20147

✦ Synopsis

Abstract

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.