{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:23:04Z","timestamp":1792905784621,"version":"4.5.0"},"reference-count":72,"publisher":"American Society of Hematology","issue":"13","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,3,27]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether \u03b1-ketoglutarate (\u03b1KG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the \u03b1KG dehydrogenase complex, which catalyzes the conversion of \u03b1KG 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 \u03b1KG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of \u03b1KG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, whereas cellular bioenergetics was largely preserved. Additionally, increased \u03b1KG levels after OGDH inhibition affected the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability, amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024025245","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T08:08:24Z","timestamp":1736496504000},"page":"1422-1436","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":17,"title":["\u03b1-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0249-2729","authenticated-orcid":false,"given":"Scott E.","family":"Millman","sequence":"first","affiliation":[{"name":"1Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"2Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2663-4672","authenticated-orcid":false,"given":"Almudena","family":"Chaves-Perez","sequence":"additional","affiliation":[{"name":"2Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha","family":"Janaki-Raman","sequence":"additional","affiliation":[{"name":"3Donald B. and Catherine C. 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