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

Author

Listed:
  • Margaret A. Potts

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Heidelberg)

  • Shinsuke Mizutani

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Kyoto Prefectural University of Medicine)

  • Yexuan Deng

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Heidelberg
    Nanjing University)

  • Srimayee Vaidyanathan

    (Peter MacCallum Cancer Centre
    The University of Melbourne
    University of South Australia and SA Pathology)

  • Keziah E. Ting

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Göknur Giner

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Heidelberg)

  • Shruti Sridhar

    (National University of Singapore)

  • Girija Shenoy

    (National University of Singapore)

  • Yang Liao

    (Heidelberg
    La Trobe University
    15 Innovation Walk)

  • Sarah T. Diepstraten

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andrew J. Kueh

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Heidelberg
    La Trobe University)

  • Martin Pal

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Charles Sturt University)

  • Geraldine Healey

    (The Walter and Eliza Hall Institute of Medical Research
    Heidelberg)

  • Lin Tai

    (The Walter and Eliza Hall Institute of Medical Research
    Heidelberg)

  • Zilu Wang

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The First Affiliated Hospital of Anhui Medical University)

  • Christina König

    (The Walter and Eliza Hall Institute of Medical Research
    Heidelberg)

  • Deeksha Kaloni

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lauren Whelan

    (The Walter and Eliza Hall Institute of Medical Research)

  • Michael J. G. Milevskiy

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Hannah D. Coughlan

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Giovanna Pomilio

    (The Walter and Eliza Hall Institute of Medical Research
    Peter MacCallum Cancer Centre)

  • Andrew H. Wei

    (The Walter and Eliza Hall Institute of Medical Research
    Peter MacCallum Cancer Centre)

  • Jane E. Visvader

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Anthony T. Papenfuss

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Stephen Wilcox

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Anand D. Jeyasekharan

    (National University of Singapore)

  • Wei Shi

    (Heidelberg
    La Trobe University
    15 Innovation Walk)

  • Emily J. Lelliott

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Heidelberg
    La Trobe University)

  • Gemma L. Kelly

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kristin K. Brown

    (Peter MacCallum Cancer Centre
    The University of Melbourne
    The University of Melbourne)

  • Andreas Strasser

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marco J. Herold

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Heidelberg
    La Trobe University)

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.

Suggested Citation

  • 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 & Marti, 2025. "Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62615-y
    DOI: 10.1038/s41467-025-62615-y
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    References listed on IDEAS

    as
    1. Jonathan B. Baell & David J. Leaver & Stefan J. Hermans & Gemma L. Kelly & Margs S. Brennan & Natalie L. Downer & Nghi Nguyen & Johannes Wichmann & Helen M. McRae & Yuqing Yang & Ben Cleary & H. Rache, 2018. "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth," Nature, Nature, vol. 560(7717), pages 253-257, August.
    2. Robert T. Manguso & Hans W. Pope & Margaret D. Zimmer & Flavian D. Brown & Kathleen B. Yates & Brian C. Miller & Natalie B. Collins & Kevin Bi & Martin W. LaFleur & Vikram R. Juneja & Sarah A. Weiss &, 2017. "In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target," Nature, Nature, vol. 547(7664), pages 413-418, July.
    3. Meiou Dai & Gang Yan & Ni Wang & Girija Daliah & Ashlin M. Edick & Sophie Poulet & Julien Boudreault & Suhad Ali & Sergio A. Burgos & Jean-Jacques Lebrun, 2021. "In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    4. Sebastien Martinez & Shifei Wu & Michael Geuenich & Ahmad Malik & Ramona Weber & Tristan Woo & Amy Zhang & Gun Ho Jang & Dzana Dervovic & Khalid N. Al-Zahrani & Ricky Tsai & Nassima Fodil & Philippe G, 2024. "In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Hans-Guido Wendel & Elisa de Stanchina & Jordan S. Fridman & Abba Malina & Sagarika Ray & Scott Kogan & Carlos Cordon-Cardo & Jerry Pelletier & Scott W. Lowe, 2004. "Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy," Nature, Nature, vol. 428(6980), pages 332-337, March.
    6. András Kotschy & Zoltán Szlavik & James Murray & James Davidson & Ana Leticia Maragno & Gaëtane Le Toumelin-Braizat & Maïa Chanrion & Gemma L. Kelly & Jia-Nan Gong & Donia M. Moujalled & Alain Bruno &, 2016. "The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models," Nature, Nature, vol. 538(7626), pages 477-482, October.
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