Epigenetics in myelodysplastic syndromes

Abstract

Epigenetic regulators are the largest group of genes mutated in MDS patients. Most mutated genes belong to one of three groups of genes with normal functions in DNA methylation, in H3K27 methylation/acetylation or in H3K4 methylation. Mutations in the majority of epigenetic regulators disrupt their normal function and induce a loss-of-function phenotype. The transcriptional consequences are often failure to repress differentiation programs and upregulation of self-renewal pathways. However, the mechanisms how different epigenetic regulators result in similar transcriptional consequences are not well understood. Hypomethylating agents are active in higher risk MDS patients, but their efficacy does not correlate with mutations in epigenetic regulators and the median duration of hematologic response is limited to 10-13 months. Inhibitors of histone deacetylases (HDAC) yielded disappointing results so far, questioning this approach in MDS patients. We review the clinical relevance of epigenetic mutations in MDS, discuss their functional consequences and highlight the role of epigenetic therapies in this difficult to treat disease.

Keywords: ASXL1; DNMT3A; EP300; EZH2; Epigenetics; HDAC inhibitor; Hypomethylating agent; IDH1; IDH2; KDM2B; KDM5A; KDM6A; MDS; MLL; MLL2; MLL3; MLL5; TET2; WT1.

Figure 1

Mutation frequency in epigenetic regulators in low-risk (refractory anemia (RA), refractory anemia with multilineage dysplasia (RCMD), and RCMD with ringsideroblasts (RCMD-RS) and high-risk (refractory anemia with excess of blasts (RAEB-1 and RAEB2)) WHO categories of MDS patients including mutations of oncogenic, possibly oncogenic as well as of unknown oncogenic potential. The data is based on a publication by Papaemmanuil et al. using mutation information in Supplementary Table S2. * indicates P<0.01.

Figure 2

Molecular function of epigenetic regulators that are frequently mutated in MDS. A nucleosome is shown with histone tails. Enzymes regulating H3K4 and H3K27 are shown on the right side of the graph. Yellow circles represent CpG dinucleotides and their methylation is described on the left side of the graph; Me: methylation mark; green arrows: positive regulation, red arrows: negative regulation.

Figure 3

Inhibitors in clinical development for MDS patients directed against epigenetic regulators or epigenetic modifications.