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

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 in a dose-dependent manner, while remaining well-tolerated. Mechanistically, multi-omic profiling revealed that histidine deprivation strongly suppresses SREBF2 and cholesterol biosynthesis pathways critical for leukemic proliferation, imposing a therapeutic vulnerability. Dietary cholesterol supplementation partially rescued the antileukemic effects of histidine restriction in vivo. Overall, these findings couple translational control in T-ALL to cholesterol metabolism, suggesting that defined dietary amino acid restrictions may expose broader therapeutic vulnerabilities in cancer. Overall design: Bulk RNA-seq and ribosome profiling of Jurkat and DND41 cells grown in media supplemented with different histidine concentrations.