Journal
LEUKEMIA
Volume 30, Issue 9, Pages 1861-1868Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.143
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Funding
- Austrian Science Fund (FWF) [P24130, SFB F4709-B20]
- Clinical Research Grant of the Austrian Society of Hematology and Oncology
- SFB project [F4704-B20, F4705-B20]
- Austrian Science Fund (FWF) [P 24130] Funding Source: researchfish
- Austrian Science Fund (FWF) [P24130] Funding Source: Austrian Science Fund (FWF)
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Little is known about the impact of DNA methylation on the evolution/progression of Ph+ 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. Although only similar to 600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared with controls, similar to 6500 differentially methylated CpG sites were found in samples 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 that 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 with CP-CML samples. Several of them are well-known tumor-suppressor genes or regulators of cell proliferation, and gene re-expression was observed by the use of epigenetic active drugs. Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML.
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