Pathogenesis of MDS III: The role of epigenetic modifications

Haema 2011; 2(2): 169-176

by Eleftheria Hatzimichael, Leonidas Benetatos, Evangelos Briasoulis

Department of Haematology, University Hospital of Ioannina

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The myelodysplastic syndromes (MDS), one of the most common hematopoietic malignancies are a group of diverse and heterogeneous syndromes characterized by clonal proliferation, bone marrow failure, dysplasia in one or more lineages and an increased risk of development of acute myelogenous leukemia (AML). Despite advances in the genetics that accompany the disease, the molecular causes of MDS and its peculiar clinical features remain poorly understood. Epigenetics refers to the study of clonally inherited changes in gene expression without accompanying changes in DNA sequence. Epigenetic changes have been recognized in the past decade as major drivers of the malignant phenotype. There are two main mechanisms carrying epigenetic information and altering gene expression: DNA methylation and histone modifications. MDS are characterized by epigenetic changes and are now considered to be an epigenetic as well as a genetic clonal disease. Studies of individual genes are pointing to a group of patients affected by the hypermethylator phenotype, while genome wide methylation analysis studies have shown that DNA methylation is abnormal early on in MDS and that progression of the disease is associated with accumulation of additional epigenetic events. Understanding the epigenetic changes in MDS may help determine prognosis and risk progression to AML. More studies are also needed in order to identify biomarkers that will discriminate patients that will respond to treatment with hypomethylating agents.