Based on our discovery of NFκB2′s novel function of regulating mitochondrial–nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. Here, NFKB2 is linked to acute myeloid leukemia.