MYC and leukemia: 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.