Aberrant methylation of CGIs in or near the promoter region of tumour suppressor genes represents one of the most consistent hallmarks of human cancers and these TSGs are often silenced in haematopoietic malignancies. Thus, CGI methylation represents an ideal candidate for diagnostic and prognostic cancer markers. Myelodysplastic syndromes comprise a MEDChem Express GDC-0973 heterogeneous group of bone marrow disorders affecting mainly elderly patients. A number of gene mutations and cytogenetic changes have been implicated in the pathogenesis of MDS, including mutations of RAS, TP53 and RUNX1, and more recently ASXL1, c-CBL, DNMT3A, IDH1/2, TET2, and EZH2. Nevertheless, these genetic abnormalities do not fully explain the pathogenesis of MDS because they are also commonly found in other myeloid malignancies and roughly 20 of MDS patients have no known genetic mutation. On the other hand, hypermethylation of specific genes, such as p15, E-cadherin, ER, MYOD1, and HIC1, have been noted, and whole genome studies have revealed that MDS patients contain aberrant DNA methylation in 935693-62-2 thousands of genes compared to normal haematopoietic progenitor cells. The process of cytosine methylation is reversible and may be altered by biochemical and biological manipulation, making it an attractive target for therapeutic intervention. Epigenetic therapy with hypomethylating drugs is now the standard of care for MDS. These are potent inhibitors of DNA methyltransferases and have been approved for MDS treatment. Recent efforts have focused on lowering the dosage of azacytidine and decitabine to reduce toxicity. However, the effect of low-dose treatment on the MDS methylome is still unclear. In this report, we have determined concentrations of AZA and DAC that allow prolonged treatment in a leukemic cell model, and have determined how this affects global CGI methylation using a microarray approach. Our results show that the methylome was selectively demethylated by lowdose treatments and that gene-body CGIs were more resistant to this process. We also provide evidence that prolonged lowdose AZA and DAC treatment is sustainably effective in modifying the epigenome. DNA labelling and hybridisation was performed according to the supplied pro
