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Acute myeloid leukemia (AML) underlies the uncontrolled accumulation of immature myeloid blasts. Several cytogenetic abnormalities have been associated with AML. Among these is the NUP98-HOXA9 (NA9) translocation that fuses the Phe-Gly repeats of nucleoporin NUP98 to the homeodomain of the transcription factor HOXA9. The mechanisms enabling NA9-induced leukemia are poorly understood. Here, we conducted a genetic screen in Drosophila for modifiers of NA9. The screen uncovered 29 complementation groups, including genes with mammalian homologs known to impinge on NA9 activity. Markedly, the modifiers encompassed a diversity of functional categories, suggesting that NA9 perturbs multiple intracellular events. Unexpectedly, we discovered that NA9 promotes cell fate transdetermination and that this phenomenon is greatly influenced by NA9 modifiers involved in epigenetic regulation. Together, our work reveals a network of genes functionally connected to NA9 that not only provides insights into its mechanism of action, but also represents potential therapeutic targets., Author summary Acute myeloid leukemia or AML is a cancer of blood cells. Despite significant progress in recent years, a majority of afflicted individuals still succumbs to the disease. A variety of genetic defects have been associated to AML. Among these are chromosomal translocations, which entail the fusion of two genes, leading to the production of cancer-inducing chimeric proteins. A representative example is the NUP98-HOXA9 oncoprotein, which results from the fusion of the NUP98 and HOXA9 genes. The mechanism of action of NUP98-HOXA9 remains poorly understood. Given the evolutionarily conservation of NUP98 and HOXA9 as well as basic cellular processes across multicellular organisms, we took advantage of Drosophila fruit flies as a genetic tool to identify genes that impinge on the activity of human NUP98-HOXA9. Surprisingly, this approach identified a relatively large spectrum of conserved genes that engaged in functional interplay with NUP98-HOXA9, which indicated the pervasive effects that this oncogene has on basic cellular events. While some genes have been previously linked to NUP98-HOXA9, thus validating our experimental approach, several others are novel and as such represent potentially new avenues for therapeutic intervention.