Integrating genetics and epigenetics in myelodysplastic syndromes: advances in pathogenesis and disease evolution

Abstract

The myelodysplastic syndromes (MDS) are a group of clonal diseases characterized by inefficient haematopoiesis, increased apoptosis and risk of evolution to acute myeloid leukaemia. Alterations in epigenetic processes, including DNA methylation, histone modifications, miRNA and splicing machinery, are well known pathogenical events in MDS. Although many advances have been made in determining the mutational frequency, distribution and association affecting these epigenomic regulators, functional integration to better understand pathogenesis of the disease is a challenging and expanding area. Recent studies are shedding light on the molecular basis of myelodysplasia and how mutations and epimutations can induce and promote this neoplastic process through aberrant transcription factor function (RUNX1, ETV6, TP53), kinase signalling (FLT3, NRAS, KIT, CBL) and epigenetic deregulation (TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, ZRSR2). In this review we will try to focus on the description of these mutations, their impact on prognosis, the functional connections between the different epigenetic pathways, and the existing and future therapies targeting these processes.

Keywords: epigenetics; genetics; myelodysplastic syndromes.

Figure 1

Main mutated epigenetic regulators in myelodysplastic syndrome (MDS). Genes represented in red are known to be associated with worse prognosis. Genes in green are associated with better prognosis and those in blue have an unclear prognostic impact. Percentages represent the known prevalence of the mutation in MDS.

Figure 2

Main mutated epigenetic regulators in acute myeloid leukaemia (AML). Frequencies of mutations include all AML cases (both de novo and secondary) in patients aged 60 years or younger (<60y) and older than 60 years (>60y).

Figure 3

DNA methylation and histone modifications by TET2 and DNMT3A.

Figure 4

Transcriptional regulation through PRC1, PRC2, TET2 and DNMT3A. Figures in red represent proteins known to harbour loss-of-function mutations in myelodysplastic syndrome.

Figure 5

EZH2 downregulation effects and splicing mutations in MDS. This figure represents the connection between splicing mutations, EZH2 loss of function and deregulation of proliferataion and innate immunity signalling through IRF4. Adapted from Rogers et al (2013) and Khan et al (2013). mt, mutated.