A dietary pan-amino acid dropout screen <i>in vivo</i> 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 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 <i>in vivo</i>. 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.
Authors
- S Ulrich
- Joshua D. Rabinowitz (ORCID: https://orcid.org/0000-0002-1247-4727)
- Oekyung Kim
- Maya Aleksandrova
- Dieter Lütjohann (ORCID: https://orcid.org/0000-0002-7941-8308)
- Michael Wierer (ORCID: https://orcid.org/0000-0002-0356-5571)
- Amartya Singh (ORCID: https://orcid.org/0000-0003-2422-3068)
- Eileen White (ORCID: https://orcid.org/0000-0003-2961-3065)
- Puneet Sharma (ORCID: https://orcid.org/0000-0002-7522-6480)
- Sebastian A. Leidel (ORCID: https://orcid.org/0000-0002-0523-6325)
- Daniel Herranz (ORCID: https://orcid.org/0000-0003-1768-5969)
- Raphael J. Morscher (ORCID: https://orcid.org/0000-0003-3378-9266)
- Victoria da Silva-Diz (ORCID: https://orcid.org/0000-0002-1508-2999)
- Diaz-Rubio Maria Elena
- Komal Mandleywala
- Christopher Thai
- Cristián Eggers
- Xiaoyang Su
- Tanaya Kulkarni
- Gwendolyn Chung
Institutions
- Rutgers, The State University of New Jersey (US)
- University of Bern (CH)
- University of Copenhagen (DK)
- Princeton University (US)
- University Hospital Bonn (DE)
- Johnson University (US)
- ETH Zurich (CH)
- Rutgers Sexual and Reproductive Health and Rights (NL)
- Environmental and Occupational Health Sciences Institute (US)
- University Children's Hospital Zurich (CH)
- Ludwig Cancer Research (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-23
- DOI
- https://doi.org/10.64898/2025.12.21.694897
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Rutgers Cancer Institute of New Jersey
- Regeneron Pharmaceuticals
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novo Nordisk
- EMDO Stiftung
- Hermann Klaus Stiftung
- NOMIS Stiftung
- Novo Nordisk Fonden
- Geistlich Pharma
- National Cancer Institute