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<p>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 <i>Eµ-Myc;Cas9</i> 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.</p>

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Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月21日

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  • Margaret A. Potts,
  • Shinsuke Mizutani,
  • Yexuan Deng,
  • Srimayee Vaidyanathan,
  • Keziah E. Ting,
  • Göknur Giner,
  • Shruti Sridhar,
  • Girija Shenoy,
  • Yang Liao,
  • Sarah T. Diepstraten,
  • Andrew J. Kueh,
  • Martin Pal,
  • Geraldine Healey,
  • Lin Tai,
  • Zilu Wang,
  • Christina König,
  • Deeksha Kaloni,
  • Lauren Whelan,
  • Michael J. G. Milevskiy,
  • Hannah D. Coughlan,
  • Giovanna Pomilio,
  • Andrew H. Wei,
  • Jane E. Visvader,
  • Anthony T. Papenfuss,
  • Stephen Wilcox,
  • Anand D. Jeyasekharan,
  • Wei Shi,
  • Emily J. Lelliott,
  • Gemma L. Kelly,
  • Kristin K. Brown,
  • Andreas Strasser,
  • Marco J. Herold

摘要

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.