Cytosine modifications in myeloid malignancies.

Abstract

Aberrant DNA methylation is a hallmark of many cancers, including the myeloid malignancies acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The discovery of TET-mediated demethylation of 5-methylcytosine (5mC) and technological advancements in next-generation sequencing have permitted the examination of other cytosine modifications, namely 5-hydroxymethylcytosine (5hmC), in these myeloid malignancies on a genome-wide scale. Due to the prominence of mutations in epigenetic modifiers that can influence cytosine modifications in these disorders, including IDH1/2, TET2, and DNMT3A, many recent studies have evaluated the relative levels, distribution, and functional consequences of cytosine modifications in leukemic cells. Furthermore, several therapies are being used to treat AML and MDS that target various proteins within the cytosine modification pathway in an effort to revert the abnormal epigenetic patterns that contribute to the diseases. In this review, we provide an overview of cytosine modifications and selected technologies currently used to distinguish and analyze these epigenetic marks in the genome. Then, we discuss the role of mutant enzymes, including DNMT3A, TET2, IDH1/2, and the transcription factor, WT1, in disrupting normal patterns of 5mC and 5hmC in AML and MDS. Finally, we describe several therapies, both standard, front-line treatments and new drugs in clinical trials, aimed at inhibiting the proteins that ultimately lead to aberrant cytosine modifications in these diseases.