Genome-wide in vivo CRISPR screens identify GATOR1 as a potent tumor suppressor and its loss sensitizes MYC-driven lymphomas to mTOR inhibition

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new tumor driving processes we have used a genome-wide CRISPR/Cas9 knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo . We uncovered that loss of either of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerated c-MYC-driven lymphoma development in mice, indeed to an extent comparable to loss of p53. In human lymphomas mutations or low expression of the GATOR1 complex genes were mutually exclusive with defects in p53 and correlated with poor survival outcomes for patients with high MYC-expressing cancers. Lymphomas lacking GATOR1 were highly sensitive to mTOR inhibitors, both in vitro and in vivo . These findings identify inhibition of mTORC1 as a potent tumor suppressive mechanism in c-MYC-driven lymphomagenesis, and suggest a new avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition. Statement of Significance Our in vivo CRISPR/Cas9 whole genome knockout screens identified the GATOR1 complex as a potent suppressor in c-MYC-driven lymphomagenesis. GATOR1 deficiency obviates the pressure to lose p53 during c-MYC driven lymphoma development and primes these malignant cells for heightened sensitivity to mTOR inhibition, suggesting a novel therapeutic approach. ### Competing Interest Statement The authors have declared no competing interest.