| description |
Little is known about the impact of DNA methylation on the evolution/progression of chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. While only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared to controls, ~6,500 differentially methylated CpG sites were found in cells from BC-CML patients. In the majority of affected CpG sites methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes which were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared to CP-CML-derived cells. Several of them are well-known tumor suppressor genes or regulators of cell proliferation. 5-aza-2 -deoxycytidine treatment of CML cells resulted in gene re-expression and in a dose-dependent cell growth reduction. Single nucleotide variants of certain epigenetic modifiers during CML progression were not found. Together, our results demonstrate that methylation changes occur frequently during CML progression and may provide a useful basis for revealing new targets of therapy in advanced CML. |