GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24)

✍ Scribed by Mariko Eguchi; Minenori Eguchi-Ishimae; Masao Seto; Kazuhiro Morishita; Katsuyuki Suzuki; Ryuzo Ueda; Kazuhiro Ueda; Nanao Kamada; Mel Greaves

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 211 KB
• Volume: 32
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.1185

✦ Synopsis

Abstract

We report a novel MLL‐associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase‐II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL‐GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C‐terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoint analysis showed potential in vitro topoisomerase‐II DNA‐binding sites spanning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL‐GPHN may have been generated by VP 16/topoisomerase‐II–induced DNA double‐strand breaks, followed by error‐prone DNA repair via non‐homologous end joining. Gephyrin was originally identified as a submembraneous scaffold protein that anchors and immobilizes postsynaptic membrane neurotransmitter receptors to underlying cytoskeletal elements. It also is reported to bind to phosphatidylinositol 3,4,5‐triphosphate binding proteins involved in actin dynamics and downstream signaling and interacts with ATM‐related family member RAFT1. Gephyrin domains in the chimeric protein therefore could contribute novel signal sequences or might modify MLL activity by oligomerization or intracellular redistribution. © 2001 Wiley‐Liss, Inc.