Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • June 10, 2019

Research

keywords

  • Cell Proliferation
  • Energy Metabolism
  • Lymphoma, Large B-Cell, Diffuse
  • Sirtuin 3

Identity

PubMed Central ID

  • PMC7534582

Scopus Document Identifier

  • 85066074062

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2019.05.002

PubMed ID

  • 31185214

Additional Document Info

volume

  • 35

issue

  • 6