Targeting mitochondrial TRIP13-AIF interaction suppresses myeloid leukemia progression and overcomes drug resistance.

Venetoclax-based therapies have revolutionized acute myeloid leukemia (AML) treatment, yet disease progression remains a challenge due to limited response and acquired drug resistance. Identifying molecular drivers of AML progression and resistance is essential for improving therapeutic outcomes. Genes normally silenced in normal tissues but aberrantly activated in cancers, such as Cancer-Testis (CT) genes, are promising targets for cancer diagnostics and therapy. Through a CRISPR screen focused on CT genes and cancer-associated genes exhibiting a CT-like expression profile (CT-like gene), we identified the ATPase TRIP13 as critical for AML progression while dispensable for normal hematopoiesis in genetic mouse models. Mechanistically, we discovered that TRIP13 localizes to mitochondria, where it interacts with apoptosis-inducing factor (AIF), a component of respiratory complex I. This interaction promotes leukemia progression and confers drug resistance by preventing AIF translocation to the nucleus, thereby reducing apoptotic priming and shifting energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) coupled with increased fatty acid oxidation (FAO). Genetic or pharmacological disruption of the TRIP13-AIF interaction suppressed OXPHOS, reduced leukemia cell viability, and overcame venetoclax resistance in vitro and in vivo. These findings uncover a novel mechanism by which AML cells exploit germline programs to sustain progression and resist therapy, positioning the TRIP13-AIF interaction as a promising therapeutic target for AML.