α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia Journal Article
| Authors: | Millman, S. E.; Chaves-Perez, A.; Janaki-Raman, S.; Ho, Y. J.; Morris, J. P. 4th; Narendra, V.; Chen, C. C.; Jackson, B. T.; Yashinskie, J. J.; Mezzadra, R.; Devine, T. I.; Barthet, V. J. A.; Saoi, M.; Baslan, T.; Tian, S.; Sachs, Z.; Finley, L. W. S.; Cross, J. R.; Lowe, S. W. |
| Article Title: | α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia |
| 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 blockade of de novo nucleotide biosynthesis, whereas cellular bioenergetics was largely preserved. Additionally, increased αKG 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. © 2025 American Society of Hematology |
| Keywords: | controlled study; human cell; nonhuman; mouse; cell cycle progression; animal experiment; animal model; genotype; biosynthesis; immunophenotyping; amino acid; karyotype; bioenergy; aspartic acid; bioluminescence; functional genomics; platelet count; antileukemic activity; citric acid cycle; metabolomics; aerobic metabolism; acute myeloid leukemia; nucleotide metabolism; carboxylation; oxoglutarate dehydrogenase; human; article; clustered regularly interspaced short palindromic repeat; gene set enrichment analysis; succinyl coenzyme a |
| Journal Title: | Blood |
| Volume: | 145 |
| Issue: | 13 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2025-03-27 |
| Start Page: | 1422 |
| End Page: | 1436 |
| Language: | English |
| DOI: | 10.1182/blood.2024025245 |
| PUBMED: | 39791576 |
| PROVIDER: | scopus |
| PMCID: | PMC11969269 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Scott W. Lowe -- Source: Scopus |
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