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.

Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner

“…52,53 The results of the present study provide a new mouse model for hematologic malignancies. Inactivating mutations targeting PRC2 components, such as EED and SUZ12, have recently been identified even in solid tumors.…”

Endothelial Progenitor Cell Dysfunction in Myelodysplastic Syndromes: Possible Contribution of a Defective Vascular Niche to Myelodysplasia

“…Because aberrant DNA methylation of CpG-rich promoters of a variety of genes is very frequent in MDS [17], we investigated in ECFCs an eventual deregulation of the epigenetic machinery. We examined in ECFC samples obtained from 20 patients the methylation status of four genes that frequently undergo hypermethylation in MDS hematopoietic cells: p15INK4b (p15) , DAPK1 , CDH1 , and SOCS1 .…”

Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells

“…Global DNA hypomethylation and gene-specific hypermethylation have been demonstrated to occur during the transformation of malignant cells (Baylin 2005;Ehrlich 2009). Aberrant DNA hypermethylation is suggested to correlate with the onset and progression of MDS and AML (Issa 2013;Schoofs et al 2014). Nevertheless, DNA hypomethylation signatures are also found in different genetic subtypes of AML (Saied et al 2012;Schoofs et al 2014).…”

“…Nevertheless, DNA hypomethylation signatures are also found in different genetic subtypes of AML (Saied et al 2012;Schoofs et al 2014). Most efforts have focused on the roles and mechanisms of hypermethylation of tumor suppressor genes in leukemia (Issa 2013;Schoofs et al 2014), while the functional role of the MDSand AML-linked DNA hypomethylation remains elusive. Decreased DNA methylation in AML with DNMT3A mutations is linked with higher relapse rates and an inferior overall survival (Hájková et al 2012).…”