Vitamin C Restores TET2 Activity in TET2-Deficient Leukemia

TET2 loss-of-function mutations are common in patients with myelodysplastic syndrome, acute myeloid leukemia (AML), and chronic myelomonocytic leukemia. TET2 is an α-ketoglutarate– and Fe²⁺-dependent dioxygenase (α-KGDD) that catalyzes oxidation of 5-methylcytosine (5mC) to promote DNA demethylation. TET2 mutations can promote leukemic progression and are associated with a poor prognosis in AML, suggesting the potential for pharmacologic restoration of TET2 activity. Cimmino and colleagues developed an RNAi transgenic mouse model allowing reversible Tet2 knockdown to investigate the effects of Tet2 restoration on hematopoietic cells. TET2 depletion promoted aberrant self-renewal in hematopoietic stem and progenitor cells (HSPC), and TET2 restoration reversed these effects, promoting myeloid differentiation and HSPC death. Further, TET2 restoration induced global DNA demethylation and differential expression. Gene expression analysis revealed that TET2 restoration upregulated cytoskeletal regulators, the DNA methyltransferase DNMT3b, and genes involved in apoptosis and the DNA damage response, and downregulated genes involved in cytokine signaling. Vitamin C is an α-KGDD cofactor that has been shown to increase TET catalytic activity, and vitamin C treatment phenocopied Tet2 restoration, suppressing myeloid disease progression in vivo. Further, in human AML cell lines, vitamin C enhanced TET activity, resulting in DNA hypomethylation and suggesting the possibility for high-dose vitamin C treatment in TET2-deficient malignancies. In addition, TET-mediated DNA oxidation induced by vitamin C increased the requirement for PARP and DNA repair associated with DNA demethylation in AML cells, thereby conferring sensitivity to PARP inhibitors. These findings indicate that, in TET2-deficient malignancies, TET2 restoration can block leukemic progression, and support investigation of high-dose vitamin C as a potential therapeutic strategy to restore TET2 activity. Moreover, these results suggest that TET2 restoration may enhance the sensitivity of leukemia cells to PARP inhibition, suggesting the potential for combination therapies.

Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 2017;170:1079–95.e20.

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