IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-62615-y.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-62615-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-62615-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62615-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.