NUP98-HOXA9 AND AML

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DESCRIPTION: (adapted from the investigator's abstract) The t(7;11) in patients with acute myeloid leukemia (AML) generates a fusion gene encoding the amino-terminal NUP98, an FG repeat-containing nuclear pore complex protein (NPC), and the carboxy-terminus of HOXA9, a homeotic transcription factor. The NUP98 portion of NUP98-HOXA9 contains 37 of the 38 FG repeat motif of NUP98. The HOXA9 part contains the HOXA9 DNA-binding domain and a TRP-containing motif that mediates interactions between HOXA9 and other transcription factors. The long term objective is to understand the exact mechanism by which NUP98-HOXA9 contributes to leukemia. To achieve this goal, the functionally critical motifs in the NUP98 and HOXA9 portions of NUP98-HOXA9 that mediate its ability to transform NIH3T3 cell will be defined, as will the proteins that interact with these motifs. The ability of each NUP98-HOXA9 isoform to induce AML in vivo will be tested by genetically engineering mice to express the chimeric proteins. Further, these mice will be bred onto a BXH2 genetic background to identify mutations that cooperate with NUP98-HOXA9 to induce AML. Finally, the normal in vivo functions of NUP98 and HOXA9 will be studied by examining phenotypic effects of loss- or gain-of-function mutations in mice. These studies should further our understanding of the molecular mechanism of oncogenesis in an expanding subgroup o AML patients with translocations that link nucleoporins to nuclear proteins.