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Dysregulation of the TET family of epigenetic regulators in hematopoietic malignancies

Chan-Wang J. Lio, Hiroshi Yuita and Anjana Rao

Abstract

DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting, X-chromosome inactivation and cancer. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands (CGIs); these changes are often correlated with promoter hypermethylation leading to decreased expression of tumor suppressor genes, as well as with genome instability leading to amplification and aberrant expression of oncogenes. Ten-Eleven-Translocation (TET) proteins are a-ketoglutarate (αKG)-dependent dioxygenases that oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and the further oxidation products 5-formylcytosine and 5-carboxylcytosine; together, these oxidized methylcytosines (oxi-mCs) are intermediates in DNA demethylation. TET2 is frequently mutated in diverse lymphoid and myeloid cancers, and TET loss-of-function is often observed in the absence of coding region mutations in TET genes. Despite our understanding of the biochemical activities of TET proteins, how TET loss-of-function promotes the onset and progression of hematopoietic malignancies is largely unknown. Here, we review recent advances in our understanding of the role of TET enzymes in lymphoid and myeloid neoplasms, and highlight the importance of metabolic alterations that decrease TET activity in cancer initiation and progression.

  • Submitted January 17, 2019.
  • Revision received August 28, 2019.
  • Accepted July 9, 2019.