DNA Methylation as an Epigenetic Factor in the Development and Progression of Polycythemia Vera. Final Report September 15, 2005-May 14, 2009

摘要

Clonal myeloproliferative disorders (MPD) affect erythroid, myelomonocytic, and megakaryocytic lineages. An activating somatic mutation of JAK2 tyrosine kinase is present in the majority of polycythemia vera (PV) patients but also in 50% of patients with essential thrombocythemia (ET) and myelofibrosis (MF). Additonal factors are presumed to affect the phenotype and progression of the disease. We studied DNA methylation as a possible epigenetic factor in the development and progression of MPDs. We cloned 19 unique CpG islands in promoter/exon-1 regions of 15 known genes, and 4 predicted genes and annotated mRNAs as hypermethylated in PV. Using a genome-wide microarray approach, we showed distinct methylation signatures affecting hundreds of genes in MPD. We confirmed increased methylation of progesterone receptor, cadherin precursor (CDH13) and several HOX genes in MPD patients. We showed that a functional block of progesterone receptor in normal erythroid cells increased their sensitivity to erythropoietin. We demonstrated molecular responses clearing both genetic and epigenetic abnormalities after DNA-demethylation therapy in MPD patients.