美国康奈尔医学院Ari M. Melnick和Hening Lin研究组合作发现，对SIRT3的非癌基因依赖在淋巴瘤发生中起到关键作用。相关论文于2019年6月发表在国际学术期刊《Cancer Cell》杂志上。

弥漫性大B细胞淋巴瘤（DLBCL）起源于生发中心的B细胞，是具有遗传异质性与高增殖性的肿瘤。

研究人员发现，不管是何种亚型与遗传背景，DLBCL均依赖于线粒体赖氨酸去乙酰化酶SIRT3进行增殖、存活、自我更新以及体内生长。在VavP-Bcl2小鼠模型中敲除SIRT3能够降低B细胞淋巴癌的发生而不影响正常的生发中心形成。从机理上讲，SIRT3敲除通过影响依赖谷氨酸脱氢酶的谷氨酰胺到三羧酸（TCA）循环代谢途径，并降低乙酰辅酶A代谢池，从而引起自噬与细胞死亡。研究人员进一步开发了一个SIRT3的抑制剂——YC8-02，这个抑制剂能够表型模拟SIRT3的敲除并杀死DLBCL细胞。因此，这项工作建立了SIRT3作为非癌基因依赖的DLBCL代谢治疗靶点。

附：英文原文

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

Author: Meng Li, Ying-Ling Chiang, Costas A. Lyssiotis, Michael R. Green, Hening Lin, Ari M. Melnick

Issue&Volume: Jun 10, 2019 Volume 35Issue 6

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.

DOI: https://doi.org/10.1016/j.ccell.2019.05.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30240-5