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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. Li et al. show that SIRT3 is required for diffuse large B cell lymphomas (DLBCLs) but not normal germinal center B cells. SIRT3 depletion induces DLBCL cell death by reducing glutamine flux to the TCA cycle and acetyl-CoA pools. They develop a sirtuin inhibitor that mimics SIRT3 depletion and kills DLBCL cells.

Original publication

DOI

10.1016/j.ccell.2019.05.002

Type

Journal article

Journal

Cancer Cell

Publication Date

10/06/2019

Volume

35

Pages

916 - 931.e9