In this regard, we reasoned that targeting the key transcriptional regulators, such as NFκB2, and shutting down NFκB2-mediated mitochondrial–nuclear genomic crosstalk responsible for metabolic homeostasis could be more effective in inhibiting blast metabolism and overcoming drug resistance when treating AML than targeting the individual components of mitochondrial or glycolytic pathways alone [78,79]. The gene discussed is NFKB2; the disease is acute myeloid leukemia.