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Blood Cancer J. 2017 Jul 21;7(7):e587. doi: 10.1038/bcj.2017.65.

Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells.

Author information

1
Division of Hematology, Mayo Clinic, Rochester, MN, USA.
2
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Biochemistry and Developmental &Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
4
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Abstract

The Ten Eleven Translocation (TET) enzymes have been found to be mutated in both diffuse large B-cell (DLBCL) and peripheral T-cell (PTCL) lymphomas resulting in DNA hypermethylation. Recent studies in embryonal stem cells showed that ascorbic acid (AA) is a cofactor for TET with a binding site at the catalytic domain, and enhances TET activity. We hypothesized that AA could potentially enhance TET activity in lymphoma cells to cause DNA demethylation, reactivate expression of tumor suppressor genes and enhance chemosensitivity. We demonstrate in vitro that AA treatment of DLBCL and PTCL cells using AA concentrations achievable intravenously increased TET activity leading to DNA demethylation. This epigenetic effect is independent of hydrogen peroxide. AA treatment increased the expression of SMAD1, a tumor suppressor gene known to be suppressed by methylation, and increased chemosensitivity of lymphoma cells. Twenty-nine percent (10/34) of unselected lymphoma patients had plasma AA levels that were deficient suggesting an additional clinical mechanism of TET hypofunction. These data indicate that AA has the potential to modify TET function in lymphoma and enhance chemosensitivity. In addition, the AA deficiency seen in some patients may further impair TET function and contribute to resistance. Clinical trials testing intravenous AA with chemotherapy are warranted.

PMID:
28731456
PMCID:
PMC5549257
DOI:
10.1038/bcj.2017.65
[Indexed for MEDLINE]
Free PMC Article

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