title: Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia.
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.
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Heller
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Topakian
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Altenberger
authors.affiliation: Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Herndlhofer
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Ziegler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Datlinger
authors.affiliation: Children's Cancer Research Institute, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Byrgazov
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.|Max Planck Institute for Informatics, Saarbrücken, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bock
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Mannhalter
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.|Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Hörmann
authors.affiliation: Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: W R
authors.initials: WR
authors.lastname: Sperr
authors.affiliation: Children's Cancer Research Institute, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Lion
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: C C
authors.initials: CC
authors.lastname: Zielinski
authors.affiliation: Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Zöchbauer-Müller
mesh_terms: D001773:Blood Cells / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology