Epigenetics in myeloproliferative neoplasms

Abstract

The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations drive proliferative disease resulting in increased blood counts and in some cases end-stage myelofibrosis. Epigenetic changes are the reversible modifications to DNA- and RNA-associated proteins that impact gene activity without changing the DNA sequence. This review summarizes mechanisms of epigenetic changes and the nucleosome. The drivers and epigenetic regulators in MPNs are outlined. In MPNs, distinct patterns of epigenetic dysregulation have been seen in chronic and in advanced phases. Methylation age and histone modification are altered in MPNs and by further treatment. The alterations found in methylation age in MPNs and with treatment are discussed, and the changes in histone modification with Janus kinase (JAK) inhibition are evaluated. Currently available therapeutic areas where the epigenome can be altered are outlined. Thus, we review the current knowledge and understanding of epigenetics in MPN and consider further management options. Understanding the epigenome and its alteration in MPNs and epigenetic changes associated with the progression of disease will lead to advances in therapeutic options.

Keywords: DNA methylation; JAK2; NFE2; epigenetics; histone modification; myeloproliferative neoplasms.

Figure 1

The structure of the nucleosome. Represented are the eight histone proteins that form the core of the histone along with histone H1. Various methylation marks are illustrated on the N terminal amino acid chains depicting examples of the more common and best characterized posttranslational histone modifications that impact DNA transcription. K4me1–Lysine 4 mono-methylation is considered mark of active and primed enhancers. K27me3–Lysine 27 trimethylation is a mark of gene repression.

Figure 2

DNA methylation. The DNA methyltransferase (DNMT) enzymes are responsible for the conversion of cytosine to 5-methylcytosine (5-MC) that at promoter regions acts to repress transcription. Ten-eleven translocation (TET) enzymes convert 5-MC to 5-hydroxymethylcytosine (5-HMC) that acts to de-repress transcription. Isocitrate dehydrogenase (IDH) proteins convert isocitrate to α-ketoglutarate that the TET2 is dependent on. The balance of unmethylated, methylated, and 5-hydroxy methylated cytosines present in promoter regions will ultimately determine the transcriptional activation of the gene.

Figure 3

Epigenetic therapies in clinical trials in MPN. This figure summarizes the classes of epigenetic drugs being considered for or recently in trial for MPN patients.