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Leukemia. 2016 Sep;30(9):1861-8. doi: 10.1038/leu.2016.143. Epub 2016 May 23.

Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia.

Author information

1
Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.
2
Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
3
Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
4
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
5
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
6
Children's Cancer Research Institute, Vienna, Austria.
7
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
8
Max Planck Institute for Informatics, Saarbrücken, Germany.
9
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

Abstract

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 ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared with controls, ~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.

PMID:
27211271
PMCID:
PMC5240019
DOI:
10.1038/leu.2016.143
[Indexed for MEDLINE]
Free PMC Article

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