Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia
| Autor: | Fadhel M. Lafta, Laura Woodhouse, Gordon Strathdee, Helen Marr, Scott Marshall, Elaine Willmore, Timothy M. Barrow, Susan J. Tudhope, Kateryna Bilotkach, Nick Bown, Jonathan P. Wallis, Sirintra Nakjang, Gesa Junge |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Oncology
Epigenomics Male Cancer Research medicine.medical_specialty Chronic lymphocytic leukaemia Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Genetics research Cancer genomics Medicine Humans Epigenetics Homeodomain Proteins sub_healthsciences DNA methylation business.industry Epigenome Leukemia Lymphocytic Chronic B-Cell Fludarabine Differentially methylated regions chemistry MAFB Drug Resistance Neoplasm 030220 oncology & carcinogenesis Ibrutinib Female Neoplasm Recurrence Local Idelalisib business sub_biomedicalsciences medicine.drug Transcription Factors |
| Zdroj: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| Popis: | Background Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy. Methods Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro. Results We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib. Conclusion Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink