DNA Methylation as an Epigenetic Factor in the Development and Progression of Polycythemia Vera

Abstract

Abstract : Polycythemia vera (PV) is the most common myeloproliferative disorder with a yearly incidence of 28 per 1 million people and a slightly higher prevalence in males. PV is characterized by clonal expansion of erythroid, myelomonocytic, and megakaryocytic lineages, erythrocytosis being the most prominent clinical manifestation of PV. The disease is associated with a significant morbidity and mortality, including thrombotic and/or hemorrhagic events, and a risk of an evolution into myelofibrosis and leukemia. An acquired activating V617F (1849G>T) mutation of JAK2 tyrosine kinase has been recently found in the majority of patients with polycythemia vera (PV), in about half of those with essential thrombocythemia (ET) and myelofibrosis (MF), and in 10-20% patients with chronic myelomonocytic leukemia, Philadelphia-negative CML, atypical or unclassified myeloproliferative diseases (MPD) and megakaryocytic leukemia. It is not known what other factors determine the disease phenotype of PV, MF, and other MPD, and what factors other than JAK2 lead to disease progression. Very little is known about epigenetic changes in PV. Epigenetic lesions have been recognized to be important in cancer, in particular in older individuals. Methylation of cytosines in the CpG sites clustered in the gene promoter regions results in epigenetic gene silencing, and acts as one of possible mechanisms of tumor suppressor inactivation in cancer. Diverse myeloproliferative phenotypes caused by a single point mutation of JAK2 tyrosine kinase, lack of other genetic specific lesions in PV, and its association with higher age lead us to propose the hypothesis that epigenetic silencing may play a role in the pathogenesis of PV.