Year: 2026
Type: preprint
Abstract: 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.
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
Funders: American Cancer Society, Moody Foundation, American Society of Hematology, Alex's Lemonade Stand Foundation for Childhood Cancer, Rally Foundation, Cancer Prevention and Research Institute of Texas, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W7223157345