Publications
Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia
TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a
worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2
activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes
active DNA demethylation via base excision repair (BER), which slows leukemia progression.
We utilize genetic and compound library screening approaches to identify rational combination
treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In
addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved
drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits
a strong synergistic effect to block AML self-renewal in murine and human AML models.
Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound
PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle
stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression,
vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
Epigenetic Regulation of Genomic Stability by Vitamin C
DNA methylation plays an important role in the maintenance of genomic stability. Ten-eleven
translocation proteins (TETs) are a family of iron (Fe2+) and α-KG -dependent dioxygenases
that regulate DNA methylation levels by oxidizing 5-methylcystosine (5mC) to generate
5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC).
These oxidized methylcytosines promote passive demethylation upon DNA replication, or active
DNA demethylation, by triggering base excision repair and replacement of 5fC and 5caC
with an unmethylated cytosine. Several studies over the last decade have shown that loss
of TET function leads to DNA hypermethylation and increased genomic instability. Vitamin C,
a cofactor of TET enzymes, increases 5hmC formation and promotes DNA demethylation, suggesting
that this essential vitamin, in addition to its antioxidant properties, can also directly
influence genomic stability. This review will highlight the functional role of DNA methylation,
TET activity and vitamin C, in the crosstalk between DNA methylation and DNA repair.
