Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62615-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Margaret A. Potts |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e8cf85c6b6634be99a253532743f4ca5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e8cf85c6b6634be99a253532743f4ca52025-08-24T11:37:08ZengNature PortfolioNature Communications2041-17232025-08-0116111410.1038/s41467-025-62615-yGenome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphomaMargaret A. Potts0Shinsuke Mizutani1Yexuan Deng2Srimayee Vaidyanathan3Keziah E. Ting4Göknur Giner5Shruti Sridhar6Girija Shenoy7Yang Liao8Sarah T. Diepstraten9Andrew J. Kueh10Martin Pal11Geraldine Healey12Lin Tai13Zilu Wang14Christina König15Deeksha Kaloni16Lauren Whelan17Michael J. G. Milevskiy18Hannah D. Coughlan19Giovanna Pomilio20Andrew H. Wei21Jane E. Visvader22Anthony T. Papenfuss23Stephen Wilcox24Anand D. Jeyasekharan25Wei Shi26Emily J. Lelliott27Gemma L. Kelly28Kristin K. Brown29Andreas Strasser30Marco J. Herold31The Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchPeter MacCallum Cancer CentrePeter MacCallum Cancer CentreThe Walter and Eliza Hall Institute of Medical ResearchDepartment of Hematology-Oncology, National University Hospital and Cancer Science Institute of Singapore, National University of SingaporeDepartment of Hematology-Oncology, National University Hospital and Cancer Science Institute of Singapore, National University of SingaporeOlivia Newton-John Cancer Research Institute, HeidelbergThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchDepartment of Hematology-Oncology, National University Hospital and Cancer Science Institute of Singapore, National University of SingaporeOlivia Newton-John Cancer Research Institute, HeidelbergThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchPeter MacCallum Cancer CentreThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchAbstract 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.https://doi.org/10.1038/s41467-025-62615-y |
| spellingShingle | 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 Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma Nature Communications |
| title | Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma |
| title_full | Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma |
| title_fullStr | Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma |
| title_full_unstemmed | Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma |
| title_short | Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma |
| title_sort | genome wide in vivo crispr screens identify gator1 complex as a tumor suppressor in myc driven lymphoma |
| url | https://doi.org/10.1038/s41467-025-62615-y |
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