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

Highlights

• SIRT3 is highly expressed and linked to unfavorable outcome in DLBCL

• SIRT3 is required for anaplerotic metabolism in DLBCL by enhancing GDH activity

• Loss of Sirt3 impairs lymphomagenesis and prolongs survival of VavP-Bcl2 mice

• Selective inhibition of SIRT3 by YC8-02 kills DLBCLs in vitro and in vivo

Summary

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.