5-Azacytidine modulates CpG methylation levels of EZH2 and NOTCH1 in myelodysplastic syndromes
| Autor: | Thomas Ernst, Jenny Rinke, Anja L Gawlitza, Andreas Hochhaus, Elena K Müller, Roman Sajzew, Johanna Speith, Vivien Schäfer |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Antimetabolites Antineoplastic Cancer Research Myeloid Azacitidine Chronic myelomonocytic leukemia Biology 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Biomarkers Tumor Tumor Cells Cultured medicine Humans Enhancer of Zeste Homolog 2 Protein Epigenetics Receptor Notch1 Aged Gene Expression Profiling Myelodysplastic syndromes EZH2 Leukemia Myelomonocytic Chronic General Medicine Methylation DNA Methylation Middle Aged Prognosis medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology Case-Control Studies Myelodysplastic Syndromes 030220 oncology & carcinogenesis DNA methylation Cancer research CpG Islands Female Follow-Up Studies medicine.drug |
| Zdroj: | Journal of Cancer Research and Clinical Oncology. 145:2835-2843 |
| ISSN: | 1432-1335 0171-5216 |
| Popis: | Molecular mechanisms of response to hypomethylating agents in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) still remain largely unknown. Therefore, the effects of 5-Azacytidine (Aza) on clonal architecture and DNA methylation were investigated in this study. Using next-generation sequencing (NGS), 30 myeloid leukemia-associated genes were analyzed in 15 MDS/CMML patients with excellent response to Aza. Effects on methylation levels were analyzed by quantitative methylation analysis using pyrosequencing for the global methylation marker LINE-1 in patients and myeloid cell lines. Various myeloid cell lines and a healthy cohort were screened for methylation levels in 23 genes. Selected targets were verified on the MDS/CMML cohort. The study presented here showed a stable variant allele frequency and stable global methylation levels in responding patients. A significant demethylation of EZH2 and NOTCH1 was revealed in patients with Aza response. A response to Aza is not associated with eradication of malignant clones, but rather with a stabilization of the clonal architecture. We suggest changes in CpG methylation levels of EZH2 and NOTCH1 as potential targets of epigenetic response to Aza treatment which may also serve as useful biomarkers after clinical evaluation. |
| Databáze: | OpenAIRE |
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