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

Potts, MA; Mizutani, S; Deng, Y; Vaidyanathan, S; Ting, KE; Giner, G; Sridhar, S; Shenoy, G; Liao, Y; Diepstraten, ST; Kueh, AJ; Pal, M; Healey, G; Tai, L; Wang, Z; K&#246;nig, C; Kaloni, D; Whelan, L; Milevskiy, MJG; Coughlan, HD; Pomilio, G; Wei, AH; Visvader, JE; Papenfuss, AT; Wilcox, S; Jeyasekharan, AD; Shi, W; Lelliott, EJ; Kelly, GL; Brown, KK; Strasser, A; Herold, MJ

Author(s): Potts, MA; Mizutani, S; Deng, Y; Vaidyanathan, S; Ting, KE; Giner, G; Sridhar, S; Shenoy, G; Liao, Y; Diepstraten, ST; Kueh, AJ; Pal, M; Healey, G; Tai, L; Wang, Z; König, C; Kaloni, D; Whelan, L; Milevskiy, MJG; Coughlan, HD; Pomilio, G; Wei, AH; Visvader, JE; Papenfuss, AT; Wilcox, S; Jeyasekharan, AD; Shi, W; Lelliott, EJ; Kelly, GL; Brown, KK; Strasser, A; Herold, MJ;
Details: Publication Year 2025-08-21,Volume 16,Issue #1,Page 7582
Journal Title: Nature Communications
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: Animals; *Lymphoma/genetics/metabolism/pathology; Mice; Mechanistic Target of Rapamycin Complex 1/metabolism/genetics; *Proto-Oncogene Proteins c-myc/genetics/metabolism; Humans; CRISPR-Cas Systems; TOR Serine-Threonine Kinases/metabolism; *Genes, Tumor Suppressor; Mice, Knockout; Clustered Regularly Interspaced Short Palindromic Repeats; Cell Line, Tumor; Signal Transduction; Tumor Suppressor Proteins/genetics/metabolism; GTPase-Activating Proteins/genetics/metabolism; Mice, Transgenic
Department(s): Haematology; Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41467-025-62615-y
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-62615-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-09-09 06:01:16

Last Modified: 2025-09-09 06:01:24