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

N. Shenoy, T. Bhagat, E. Nieves, M. Stenson, J. Lawson, G. S. Choudhary, Thomas Matthew Habermann, Grzegorz S Nowakowski, Ravinder Jit Singh, X. Wu, A. Verma, Thomas Elmer Witzig

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e587
JournalBlood Cancer Journal
Volume7
Issue number7
DOIs
StatePublished - Jul 21 2017

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Epigenomics
Ascorbic Acid
Lymphoma
Up-Regulation
Tumor Suppressor Genes
DNA
B-Lymphocytes
Ascorbic Acid Deficiency
Peripheral T-Cell Lymphoma
Hydrogen Peroxide
Methylation
Catalytic Domain
Stem Cells
Binding Sites
Clinical Trials
T-Lymphocytes
Drug Therapy
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. / Shenoy, N.; Bhagat, T.; Nieves, E.; Stenson, M.; Lawson, J.; Choudhary, G. S.; Habermann, Thomas Matthew; Nowakowski, Grzegorz S; Singh, Ravinder Jit; Wu, X.; Verma, A.; Witzig, Thomas Elmer.

In: Blood Cancer Journal, Vol. 7, No. 7, 21.07.2017, p. e587.

Research output: Contribution to journalArticle

Shenoy, N. ; Bhagat, T. ; Nieves, E. ; Stenson, M. ; Lawson, J. ; Choudhary, G. S. ; Habermann, Thomas Matthew ; Nowakowski, Grzegorz S ; Singh, Ravinder Jit ; Wu, X. ; Verma, A. ; Witzig, Thomas Elmer. / Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. In: Blood Cancer Journal. 2017 ; Vol. 7, No. 7. pp. e587.
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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.",
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