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

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 aft er intensive chemotherapy, that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a no vel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. Th e resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methy ltransferase homology domain fused to the C-terminal half of Gephyrin, incl uding a presumed tubulin binding site and a domain homologous to the Escher ichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoin t analysis showed potential, in vitro topoisomerase-II DNA-binding sites sp anning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL-GPHN may hav e been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks , followed by error-prone DNA repair via non-homologous end joining. Gephyr in was originally identified as a submembraneous scaffold protein that anch ors and immobilizes postsynaptic membrane neurotransmitter receptors to und erlying cytoskeletal elements. It also is reported to bind to phosphatidyli nositol 3,4,5-triphosphate binding proteins involved in actin dynamics and downstream signaling and, interacts with ATM-related family member RAFTI. G ephyrin domains in the chimeric protein therefore could contribute novel si gnal sequences or might modify MLL activity by oligomerization or intracell ular redistribution. (C) 2001 Wiley-Liss, Inc.