Manipulation of Mitochondrial Metabolism Sensitizes AML to MCL-1 Inhibition

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes such as those harboring KMT2A rearrangements (KMT2A-r). Clinical trials of MCL-1 inhibitors have been limited by modest efficacy and dose-limiting toxicity, underscoring the need for rational combination strategies. Here, we identify inhibition of electron transport chain complex I (CI) as a synthetic lethal partner for MCL-1 blockade. Mechanistically, CI suppression activates the mitochondrial stress arm of the integrated stress response (ISR), sensitizing leukemia cells to apoptosis upon MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML.