A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL

Abstract Dietary interventions show therapeutic potential in cancer, but systematic comparisons are lacking. We performed a dietary pan-amino acid dropout screen in an orthotopic model of NOTCH1-driven T-cell acute lymphoblastic leukemia and identified histidine depletion as uniquely antileukemic. Histidine-restricted diets extended survival of leukemic mice in a dose-dependent manner, while remaining well-tolerated. Mechanistically, multiomic profiling revealed that histidine deprivation-induced ribosome stalling activates GCN2 to suppress cholesterol biosynthesis pathways critical for leukemic proliferation. Dietary cholesterol supplementation partially reverted the antileukemic effects of histidine restriction in vivo. These findings couple histidine levels and translational control to cholesterol metabolism, which can be therapeutically exploited for cancer treatment. Our results suggest that defined dietary amino acid restrictions may expose broader therapeutic opportunities in diseases beyond cancer. Competing Interest Statement The authors have declared no competing interest. Footnotes Financial support: Work in the laboratory of D.H. is supported by the US National Institutes of Health (R01CA236936 and R01CA285513), Blood Cancer United, formerly The Leukemia & Lymphoma Society (Scholar Award 1386-23), the V Foundation (T2023-024), the Alex’s Lemonade Stand Foundation (R Award 23-28273), the Ludwig Cancer Research Princeton Branch, the New Jersey Commission on Cancer Research (COCR23PRG006) and the Rutgers Cancer Institute of New Jersey. In addition, Rutgers Cancer Institute of New Jersey shared resources supported in part by the National Cancer Institute Cancer Center Support Grant P30CA072720 were instrumental for this project, including the Metabolomics Shared Resource (P30CA072720-5923) and the Pilot Award/New Investigator Award (P30CA072720-5931). Fellowships from the New Jersey Commission on Cancer Research supported the work of K.M. (COCR24PRF011), V.dD. (DCHS19PPC008 and COCR22PDF002) and A.S. (COCR24PDF015). V.dD. and A.S. were also supported by the New Jersey Pediatric Hematology and Oncology Research Center of Excellence (NJ PHORCE) at the Rutgers Cancer Institute of New Jersey. Work in the laboratory of R.J.M. is supported by grants from the Prof. Dr. Max Cloëtta Foundation, Horten Foundation, NOMIS Foundation, Geistlich Stucki Stiftung, I Ging Stiftung, Fores Stiftung, Hermann Klaus Stiftung, Gertrud-Hagmann-Stiftung für Malignom-Forschung, EMDO-Stiftung and Heidi Ras Grant of the FZK University Children’s Hospital Zürich. Swiss National Science Foundation project number 221617. This article/publication is based upon work from COST Action Translational control in Cancer European Network (TRANSLACORE) CA21154 supported by COST (European Cooperation in Science and Technology). S.U. was supported by a Swiss Government Excellence Scholarship and the Lab Exchange Program of the NCCR RNA & Disease. S.A.L. was supported by Swiss National Science Foundation grant 320030-236130 and 310030_219536.