They show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark, and expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at aberrant regions and up-regulation of associated genes due to aberrant Wdr82/Set1A activity. Here, SETD1A is linked to acute myeloid leukemia.