The myelodysplastic syndrome as a prototypical epigenetic disease

Abstract

The myelodysplastic syndrome (MDS) is a clonal disorder characterized by increased stem cell proliferation coupled with aberrant differentiation resulting in a high rate of apoptosis and eventual symptoms related to bone marrow failure. Cellular differentiation is an epigenetic process that requires specific and highly ordered DNA methylation and histone modification programs. Aberrant differentiation in MDS can often be traced to abnormal DNA methylation (both gains and losses of DNA methylation genome wide and at specific loci) as well as mutations in genes that regulate epigenetic programs (TET2 and DNMT3a, both involved in DNA methylation control; EZH2 and ASXL1, both involved in histone methylation control). The epigenetic nature of MDS may explain in part the serendipitous observation that it is the disease most responsive to DNA methylation inhibitors; other epigenetic-acting drugs are being explored in MDS as well. Progression in MDS is characterized by further acquisition of epigenetic defects as well as mutations in growth-controlling genes that seem to tip the proliferation/apoptosis balance and result in the development of acute myelogenous leukemia. Although MDS is clinically and physiologically heterogeneous, a case can be made that subsets of the disease can be largely explained by disordered stem cell epigenetics.

Figure 1

Origin of aberrant epigenetic programs in MDS. MDS carries an altered epigenome that results in stable gene expression changes represented by a heatmap on the right side of the figure. These can be influenced by DNA methylation (5mC) and histone code posttranslational modifications such as histone H3 lysine 27 trimethylation (H3K27me3) and acetylation (Ac) of multiple residues on histone H3 and H4. Cytosine hydroxymethylation (5hmC) influences 5mC content and may have direct effects on gene expression (arrow with a question mark). There are also complex correlations between DNA methylation and histone modifications. Molecularly, 5hmC can be altered by TET2 mutations, 5mC is altered by age-related drift and possibly by DNMT3a mutations, and H3K27me3 is potentially influenced by ASXL1 and EZH2 mutations. However, the precise links between TET2 mutations, DNMT3a mutations, and DNA methylation in MDS remain somewhat uncertain (illustrated by dotted lines). Changes in micro-RNA expression (due to genetic or epigenetic lesions) also influence the final gene expression patterns and it is possible (though speculative) that spliceosome mutations also do this. It remains unclear how much of the final MDS gene expression patterns are driven by the described epigenetic alterations, and the heterogeneity of the disease implies that these mechanisms may be more important in some cases than in others.

Figure 2

A model of MDS formation and progression. It is hypothesized that the altered differentiation programs and dysplasias pathognomonic of MDS are due to aberrant epigenetic regulation (summarized in Figure 1). These differentiation defects signal compensatory stem cell growth but also result in increased apoptosis, which explains the paradox of hypercellular marrows but peripheral cytopenias in MDS. With time, MDS cells acquire mutations that confer uncontrolled growth signals (eg, NRAS) and/or inhibited apoptosis (eg, P53). These mutations (and, possibly additional epigenetic defects) lead to the blast expansion and inhibited differentiation characteristic of the transition from MDS to AML.