ArticleLeukemia2026
Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
Article in Leukemia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
12 authors.
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Abstract
Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.
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