Different NUP98-fusion proteins regulate a common core of transcriptional targets. (A) Schematic illustration of the experimental workflow to investigate NUP98-fusion protein-dependent transcriptional programs. NUP98-fusion–protein-driven leukemia cells were transplanted into secondary recipient mice. Mice were treated with Dox for 3 or 5 days after an initial engraftment phase of 15 days; leukemia cells were sorted from the bone marrow based on GFP/CD45.2 expression, and gene expression was analyzed by RNA-seq (n ≥ 3). (B) Representation of dynamics of global gene expression changes after 3 and 5 days of Dox-induced NUP98-fusion–protein-repression. Each line represents the harmonized mean of the median expression of all genes within the cluster of distinct fusion-protein–driven cancer cells. Maximum/minimum medians are indicated by the colored area. (C) GSEA indicating induction of myeloid differentiation upon fusion protein withdrawal. (D) Heat map of 339 commonly up- and downregulated genes in all 3 NUP98-fusion–protein-driven models after 5 days of Dox-mediated fusion-protein repression (≥1.5-fold change, P < .01). (E) GSEA illustrating the enrichment of HOXA9/MEIS1-target genes in cells expressing NUP98/NSD1.