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

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 () and Marco J. Herold ()
Additional contact information
Margaret A. Potts: The Walter and Eliza Hall Institute of Medical Research
Shinsuke Mizutani: The Walter and Eliza Hall Institute of Medical Research
Yexuan Deng: The Walter and Eliza Hall Institute of Medical Research
Srimayee Vaidyanathan: Peter MacCallum Cancer Centre
Keziah E. Ting: Peter MacCallum Cancer Centre
Göknur Giner: The Walter and Eliza Hall Institute of Medical Research
Shruti Sridhar: National University of Singapore
Girija Shenoy: National University of Singapore
Yang Liao: Heidelberg
Sarah T. Diepstraten: The Walter and Eliza Hall Institute of Medical Research
Andrew J. Kueh: The Walter and Eliza Hall Institute of Medical Research
Martin Pal: The Walter and Eliza Hall Institute of Medical Research
Geraldine Healey: The Walter and Eliza Hall Institute of Medical Research
Lin Tai: The Walter and Eliza Hall Institute of Medical Research
Zilu Wang: The Walter and Eliza Hall Institute of Medical Research
Christina König: The Walter and Eliza Hall Institute of Medical Research
Deeksha Kaloni: The Walter and Eliza Hall Institute of Medical Research
Lauren Whelan: The Walter and Eliza Hall Institute of Medical Research
Michael J. G. Milevskiy: The Walter and Eliza Hall Institute of Medical Research
Hannah D. Coughlan: The Walter and Eliza Hall Institute of Medical Research
Giovanna Pomilio: The Walter and Eliza Hall Institute of Medical Research
Andrew H. Wei: The Walter and Eliza Hall Institute of Medical Research
Jane E. Visvader: The Walter and Eliza Hall Institute of Medical Research
Anthony T. Papenfuss: The Walter and Eliza Hall Institute of Medical Research
Stephen Wilcox: The Walter and Eliza Hall Institute of Medical Research
Anand D. Jeyasekharan: National University of Singapore
Wei Shi: Heidelberg
Emily J. Lelliott: The Walter and Eliza Hall Institute of Medical Research
Gemma L. Kelly: The Walter and Eliza Hall Institute of Medical Research
Kristin K. Brown: Peter MacCallum Cancer Centre
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
Marco J. Herold: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62615-y

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