NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis

The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions. Furthermore, MLL1 is required for the proliferation of NHA9 cells in vitro and in vivo. Inactivation of MLL1 leads to decreased expression of genes bound by NHA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukemias. Our data reveal a molecular dependency on MLL1 function in NUP98-fusion-driven leukemogenesis. [Display omitted] •NUP98 fusions interact with MLL1 and NSL histone-modifying complexes•NUP98 fusions and MLL1 co-localize at Hoxa and Hoxb cluster gene loci•MLL1 is required for NUP98-HOXA9-induced leukemogenesis in vitro and in vivo•MLL1-dependent gene expression signatures resemble human NUP98-NSD1 AML Xu et al. reveal a key role for MLL1 in NUP98 fusion leukemias and show that NUP98 fusion proteins interact with MLL1 and NSL histone modifiers on chromatin to drive expression of both Hoxa and Hoxb cluster genes important for sustaining leukemia.