NUP98 regulates transcription and cell cycle progression through interactions with cofactors. (A) NUP98 fusion oncoproteins bind to various transcriptional cofactors (including XPO1, WDR-SET1-COMPASS, and/or KMT2A complexes) and remodel chromatin. This leads to expression of target genes, possibly through the formation-phase separatory transcription centers. (B) Wild-type NUP98 associates with the anaphase-promoting complex (APC/C), RAE1, and other cell-cycle proteins, contributing to regulation of the spindle-assembly checkpoint. (C) NUP98 fusion oncoproteins bind to components of the APC/C including CDC20, leading to the ubiquitination and premature degradation of securin. In turn, activation of separation causes premature spindle-assembly checkpoint. Ac, acetyl; Me, methyl; MOF, males absent on the first; NSL, nonspecific lethal; P, phospho; Ub, ubiquitin.