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Significance FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown impressive activity in clinical trials for acute myeloid leukemia (AML); however, these inhibitors invariably fail to achieve sustained remissions. Here we demonstrate that FLT3 inhibition causes severe deficiencies in redox metabolism and accumulation of reactive oxygen species (ROS) in the mitochondria of AML cells. We discovered that the metabolic regulators ataxia telangiectasia mutated and glucose 6-phosphate dehydrogenase help maintain antioxidant capacity and survival of a subpopulation of AML cells in the face of FLT3 inhibition. Inactivation of these factors escalates mitochondrial ROS and enhances AML cell eradication. Importantly, we show that the use of a drug that increases mitochondrial ROS enhances the efficacy of FLT3 inhibitor therapy, suggesting a combinatorial therapeutic strategy.
Gregory et al. (Mon,) studied this question.