髓系白血病
柠檬酸循环
生物
生物化学
脱氢酶
癌症研究
酶
作者
Scott E. Millman,Almudena Chaves Perez,Sudha Janaki‐Raman,Yu-Jui Ho,John P. Morris,Varun Narendra,Chi-Chao Chen,Benjamin T. Jackson,Jossie J. Yashinskie,Riccardo Mezzadra,Tom Devine,Valentin J.A. Barthet,Michelle Saoi,Timour Baslan,Sha Tian,Zohar Sachs,Lydia W.S. Finley,Justin R. Cross,Scott W. Lowe
出处
期刊:Blood
[American Society of Hematology]
日期:2024-12-27
标识
DOI:10.1182/blood.2024025245
摘要
Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted 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.
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