Control of Hematopoietic Stem Cells and Leukemia By Ascorbate
We have shown that hematopoietic stem cells (HSCs) in vivo accumulate high levels of ascorbate (Vitamin C), and that ascorbate is limiting for the activity of the alpha-ketoglutarate dependent dioxygenase enzyme Tet2 (Agathocleous et al., 2017). Tet2 modifies methylated cytosines on DNA, and Tet2 loss promotes HSC function and causes myeloid leukemia in mice and humans. We found that systemic or cell autonomous ascorbate depletion augments HSC function. Ascorbate is critical in restraining the expansion of hematopoietic cells that have acquired pre-leukemic mutations, and ascorbate depletion accelerates the progression of myeloid leukemia. Our observations suggest that a diet-derived metabolite alters epigenetic regulation and tumor suppression in stem cells. We are currently investigating how ascorbate depletion impacts the epigenome and genome of HSCs and leukemic cells.