Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with AML. Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via BER that slows leukemia progression. We utilized genetic and compound library screening approaches to identify rational combination treatment strategies to improve the use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several FDA approved drugs, vitamin C treatment with PARPi elicited a strong synergistic effect at blocking AML self-renewal in murine and human AML models. Vitamin C-mediated TET activation combined with PARPi caused an enrichment of chromatin-bound PARP1 at oxidized mCs, and ?H2AX accumulation during mid-S phase leading to cell-cycle stalling and differentiation. Given most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant. Overall design: Comparison of differentially expressed genes in AE9a+ leukemic cells from terminal mice treated with ascorbate and sustained Tet2 knockdown, or PBS-treated with Tet2 restoration, to PBS-treated Tet2 knockdown mice.