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

被引：92

作者：

Li, Meng ^{[1
]}

Chiang, Ying-Ling ^{[2
]}

Lyssiotis, Costas A. ^{[3
]}

Teater, Matthew R. ^{[1
]}

Hong, Jun Young ^{[2
]}

Shen, Hao ^{[1
]}

Wang, Ling ^{[1
]}

Hu, Jing ^{[2
]}

Jing, Hui ^{[2
]}

Chen, Zhengming ^{[4
]}

Jain, Neeraj ^{[7
]}

Duy, Cihangir ^{[1
]}

Mistry, Sucharita J. ^{[1
]}

Cerchietti, Leandro ^{[1
]}

Cross, Justin R. ^{[5
]}

Cantley, Lewis C. ^{[6
]}

Green, Michael R. ^{[7
]}

Lin, Hening ^{[2
,8
]}

Melnick, Ari M. ^{[1
]}

机构：

[1] Weill Cornell Med, Dept Med, Div Hematol & Med Oncol, New York, NY 10065 USA

[2] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA

[3] Univ Michigan, Dept Mol & Integrat Physiol, Med Sch, Ann Arbor, MI 48109 USA

[4] Weill Cornell Med, Div Biostat & Epidemiol, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[6] Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77005 USA

[8] Cornell Univ, Howard Hughes Med Inst, Ithaca, NY 14853 USA

来源：

CANCER CELL | 2019年 / 35卷 / 06期

关键词：

GERMINAL CENTER FORMATION; GENE-EXPRESSION; ANTITUMOR-ACTIVITY; CELL; AUTOPHAGY; CANCER; METABOLISM; INHIBITOR; SURVIVAL; REVEALS;

D O I：

10.1016/j.ccell.2019.05.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：916 / +

页数：25

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