Nonetheless, leveraging this approach, we demonstrate that (1) IRF8 and MEF2D form a distinct core regulatory module with a very narrow direct transcriptional program in KMT2Ar leukemia; (2) the IRF8/MEF2D module directly enforces expression of the key leukemia oncogenes MYC, HOXA9, and BCL2; and (3) MEF2D has partially redundant functions with its paralog, MEF2C. Here, MEF2D is linked to leukemia.