Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis

Li, M., Chiang, Y. L., Lyssiotis, C. A., Teater, M. R., Hong, J. Y., Shen, H., Wang, L., Hu, J., Jing, H., Chen, Z., Jain, N., Duy, C., Mistry, S. J., Cerchietti, L., Cross, J. R., Cantley, L. C., Green, M. R., Lin, H., & Melnick, A. M. (2019). Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Cancer cell, 35(6), 916–931.e9. https://doi.org/10.1016/j.ccell.2019.05.002

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.

Journal: Cancer Cell PMID: 31185214 DOI: 10.1016/j.ccell.2019.05.002