Using rapid targeted protein degradation coupled with nascent transcriptomics and superresolution microscopy, we demonstrate that IRF8 and MEF2D form a KMT2Ar leukemia-specific core regulatory module directly enforcing expression of the common leukemia oncogenes MYC, HOXA9, and BCL2, where MEF2D displays partial functional redundancy with its paralog, MEF2C. The gene discussed is IRF8; the disease is leukemia.