Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

Abstract

Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.

Keywords: acute myeloid leukemia (AML); chromatin; clonal hematopoiesis of indeterminate potential (CHIP); epigenetic regulators; epigenetics; myelodysplastic syndromes (MDS); secondary acute myeloid leukemia (sAML).

Figure 1

Clonal hematopoiesis in myelodysplastic syndromes (MDS) and transformation to secondary acute myeloid leukemia (sAML). Mutations in hematopoietic stem cell (HSC) clones occur at any time of our life as part of the aging process. While most mutations are background mutations that do not affect cellular properties, some mutations provide an advantage to HSCs, such as increased self-renewal. These mutations drive clonal expansion and the eventual development of the asymptomatic clonal hematopoiesis of indeterminate potential (CHIP). The further expansion frequently driven by the acquisition of additional genetic alterations can lead to MDS. The gain of additional driver mutations can further lead to transformation to sAML. This figure has been inspired by [7].

Figure 2

Overview of epigenetic drugs for MDS and sAML therapy. Many epigenetic enzymes are involved in the regulation of gene function. These can be broadly classified into “writers”, which add specific marks to core histones, namely methyl (me) and acetyl (ac) groups; “readers”, which identify the marks; and “erasers”, which remove these marks. DNA methyltransferases (DNMTs) methylate DNA, thereby silencing certain tumor suppressor gene expression. Hypomethylating agents, such as azanucleosides, are thought to reduce DNMT activity, thus reactivating silenced genes. Histone methyltransferase (HMT) inhibitors (inh) that target mutated PRMT5, DOT1L and EZH2 seek to re-stabilize perturbed histone methylation states. Histone deacetylase (HDAC) inhibitors restore histone acetylation, thus activating gene expression to promote differentiation and apoptosis. Ten-eleven translocation (TET) enzymes catalyze the demethylation of 5-methylcytosine to 5-hydroxymethylcytosine to induce active DNA demethylation. Isocitrate dehydrogenase (IDH) inhibitors reduce total serum levels of the oncometabolite, 2-hydroxyglutarate, restoring normal TET2 activity and DNA and histone methylation levels. Bromodomain and extra-terminal domain (BET) inhibitors mainly target BRD4, which normally promotes transcription of oncogenes, such as MYC, by binding acetylated histones.