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Tafazzin is a mitochondrial enzyme necessary for the remodeling of the phospholipid cardiolipin. Seneviratne and Xu et al. demonstrated that Tafazzin-mediated phospholipid production regulates stemness in Acute Myeloid Leukemia (AML). Tafazzin influenced intracellular levels of phospholipids to control AML stemness. Thus, inhibiting mitochondrial phospholipid production could be a new therapeutic strategy for AML.