全基因组体内CRISPR筛选确定GATOR1复合体为Myc驱动的淋巴瘤中的肿瘤抑制因子。
Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma.
作者信息
Potts Margaret A, Mizutani Shinsuke, Deng Yexuan, Vaidyanathan Srimayee, Ting Keziah E, Giner Göknur, Sridhar Shruti, Shenoy Girija, Liao Yang, Diepstraten Sarah T, Kueh Andrew J, Pal Martin, Healey Geraldine, Tai Lin, Wang Zilu, König Christina, Kaloni Deeksha, Whelan Lauren, Milevskiy Michael J G, Coughlan Hannah D, Pomilio Giovanna, Wei Andrew H, Visvader Jane E, Papenfuss Anthony T, Wilcox Stephen, Jeyasekharan Anand D, Shi Wei, Lelliott Emily J, Kelly Gemma L, Brown Kristin K, Strasser Andreas, Herold Marco J
机构信息
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, Australia.
出版信息
Nat Commun. 2025 Aug 21;16(1):7582. doi: 10.1038/s41467-025-62615-y.
Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC, which is abnormally highly expressed in ~70% of human cancers, we use a genome-wide CRISPR gene knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discover that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerates c-MYC-driven lymphoma development in mice. MYC-driven lymphomas lacking GATOR1 display constitutive mTOR pathway activation and are highly sensitive to mTOR inhibitors, both in vitro and in vivo. These findings identify GATOR1 suppression of mTORC1 as a tumor suppressive mechanism in MYC-driven lymphomagenesis and suggest an avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition.
鉴定肿瘤抑制基因有望为癌症治疗新策略的开发提供信息。为了确定与致癌性MYC协同作用的新的淋巴瘤驱动过程，MYC在约70%的人类癌症中异常高表达，我们在体内的Eµ-Myc;Cas9转基因造血干细胞和祖细胞中进行了全基因组CRISPR基因敲除筛选。我们发现，GATOR1复合体的任何一个组分——NPRL3、DEPDC5、NPRL2——缺失都会显著加速小鼠中c-MYC驱动的淋巴瘤发展。缺乏GATOR1的MYC驱动的淋巴瘤表现出组成型mTOR通路激活，并且在体外和体内对mTOR抑制剂高度敏感。这些发现确定了GATOR1对mTORC1的抑制是MYC驱动的淋巴瘤发生中的一种肿瘤抑制机制，并提示了通过mTOR抑制对GATOR1缺陷型淋巴瘤进行治疗干预的途径。
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