Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome, and acute myeloid leukemia and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal and blocks leukemia progression. Treatment with vitamin C, a co-factor of Fe(II) and α-ketoglutarate-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation and DNA demethylation in Tet2-deficient mouse HSPCs and human leukemia cells. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.