Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis
Li M., Chiang YL., Lyssiotis CA., Teater MR., Hong JY., Shen H., Wang L., Hu J., Jing H., Chen Z., Jain N., Duy C., Mistry SJ., Cerchietti L., Cross JR., Cantley LC., Green MR., Lin H., Melnick AM.
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.