Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

Yihong Guan, Edward F. Greenberg, Metis Hasipek, Shi Chen, Xiaochen Liu, Cassandra M. Kerr, Daniel Gackowski, Ewelina Zarakowska, Tomas Radivoyevitch, Xiaorong Gu, Belinda Willard, Valeria Visconte, Hideki Makishima, Aziz Nazha, Mridul Mukherji, Mikkael A. Sekeres, Yogen Saunthararajah, Ryszard Oliński, Mingjiang Xu, Jaroslaw P. MaciejewskiBabal K. Jha

Research output: Contribution to journalArticle

Abstract

Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

Original languageEnglish (US)
Article number493
JournalCommunications Biology
Volume3
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)
  • Medicine(all)

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    Guan, Y., Greenberg, E. F., Hasipek, M., Chen, S., Liu, X., Kerr, C. M., Gackowski, D., Zarakowska, E., Radivoyevitch, T., Gu, X., Willard, B., Visconte, V., Makishima, H., Nazha, A., Mukherji, M., Sekeres, M. A., Saunthararajah, Y., Oliński, R., Xu, M., ... Jha, B. K. (2020). Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia. Communications Biology, 3(1), [493]. https://doi.org/10.1038/s42003-020-01220-9