α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

ABSTRACT:

Abstract

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether α-ketoglutarate (αKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the αKG dehydrogenase complex, which catalyzes the conversion of αKG to succinyl coenzyme A, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the αKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of αKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and

SUBMITTER: Millman SE 

PROVIDER: S-EPMC11969269 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature