Journal
CANCER CELL
Volume 35, Issue 6, Pages 916-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.05.002
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Funding
- Leukemia & Lymphoma Society (LLS), United States (US) [SCOR 7012-16]
- Falk Medical Research Catalyst Award
- Chemotherapy Foundation
- TDI Institute Award
- Follicular Lymphoma Consortium
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Diffuse large B cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B cells. Here, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted class I sirtuin inhibitor, YC8-02, which phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.
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