Ascorbate is a physiological tumor suppressor metabolite in leukemia
- 1UT Southwestern Medical Center
Abstract
Accumulation of oncometabolites promotes tumorigenesis, but it is not known if there are naturally occurring tumor suppressor metabolites whose deficiency within cancer-initiating cells causes cancer. Many leukemia patients are ascorbate deficient. Here we show that hematopoietic-specific ascorbate depletion in mice is sufficient to cause or promote leukemogenesis. Hematopoietic-specific ascorbate depletion promoted leukemogenesis by acting within leukemia initiating cells. Ascorbate depletion in myeloid leukemia expanded plasmacytoid dendritic cells, an effect mediated by the ascorbate molecular targets TET2 and TET3. Leukemia cells accumulated ascorbate as part of a tumor suppressor response to neoplastic proliferation that limited progression but depleted circulating ascorbate. Ascorbate restoration in mice with established leukemias extended survival. Hematopoietic-specific ascorbate depletion caused leukemia in collaboration with TET2 loss and was sufficient to cause leukemia with high penetrance even in the absence of other engineered mutations. These results identify ascorbate as a physiological tumor suppressor metabolite in blood cancers.
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BibTeX
@misc{wijshake2026ascorbate,
title = {{Ascorbate is a physiological tumor suppressor metabolite in leukemia}},
author = {T. Wijshake and J. Rose and J. H. Jun and E. O. Kwarteng and X. Yang and J. Zielke and S. Mahesula and L. Li and S. S. Chung and S. Comazzetto and S. J. Morrison and W. Chen and M. Agathocleous},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760526},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760526v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Ascorbate is a physiological tumor suppressor metabolite in leukemia
AU - T. Wijshake
AU - J. Rose
AU - J. H. Jun
AU - E. O. Kwarteng
AU - X. Yang
AU - J. Zielke
AU - S. Mahesula
AU - L. Li
AU - S. S. Chung
AU - S. Comazzetto
AU - S. J. Morrison
AU - W. Chen
AU - M. Agathocleous
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760526
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760526v1
AB - Accumulation of oncometabolites promotes tumorigenesis, but it is not known if there are naturally occurring tumor suppressor metabolites whose deficiency within cancer-initiating cells causes cancer. Many leukemia patients are ascorbate deficient. Here we show that hematopoietic-specific ascorbate depletion in mice is sufficient to cause or promote leukemogenesis. Hematopoietic-specific ascorbate depletion promoted leukemogenesis by acting within leukemia initiating cells. Ascorbate depletion in myeloid leukemia expanded plasmacytoid dendritic cells, an effect mediated by the ascorbate molecular targets TET2 and TET3. Leukemia cells accumulated ascorbate as part of a tumor suppressor response to neoplastic proliferation that limited progression but depleted circulating ascorbate. Ascorbate restoration in mice with established leukemias extended survival. Hematopoietic-specific ascorbate depletion caused leukemia in collaboration with TET2 loss and was sufficient to cause leukemia with high penetrance even in the absence of other engineered mutations. These results identify ascorbate as a physiological tumor suppressor metabolite in blood cancers.
SN - 2692-8205
ER -