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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Cells / pathology
  • Bone Marrow Cells / pathology
  • Case-Control Studies
  • CpG Islands
  • DNA Methylation*
  • Disease Progression
  • Down-Regulation
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology