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

Margaret A Potts1,2,3, Shinsuke Mizutani1,2,4, Yexuan Deng1,2,3,5

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Nature Communications
|August 21, 2025
PubMed

Insights

Loss of GATOR1 complex genes accelerates MYC-driven lymphoma by activating the mTOR pathway. This discovery suggests targeting mTOR could be a new therapy for GATOR1-deficient lymphomas.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Identifying tumor suppressor genes is crucial for developing novel cancer therapies.
  • The MYC oncogene is highly expressed in many human cancers, driving tumorigenesis.
  • Understanding cooperating genetic events with MYC is key to deciphering lymphoma development.

Purpose of the Study:

  • To identify novel lymphoma-driving processes that cooperate with the oncogenic MYC.
  • To explore the role of the GATOR1 complex in MYC-driven lymphomagenesis.

Main Methods:

  • Genome-wide CRISPR gene knockout screen was performed in vivo.
  • Utilized Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells.
  • Assessed the impact of gene loss on lymphoma development and mTOR pathway activation.

Main Results:

  • Loss of GATOR1 complex components (NPRL3, DEPDC5, NPRL2) significantly accelerates MYC-driven lymphoma in mice.
  • MYC-driven lymphomas lacking GATOR1 exhibit constitutive mTOR pathway activation.
  • These lymphomas are highly sensitive to mTOR inhibitors in vitro and in vivo.

Conclusions:

  • GATOR1 complex suppresses mTORC1, acting as a tumor suppressor in MYC-driven lymphomagenesis.
  • GATOR1 deficiency in lymphomas creates a therapeutic vulnerability to mTOR inhibitors.
  • Targeting the mTOR pathway presents a potential therapeutic strategy for GATOR1-deficient lymphomas.

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