Timothy M Barrow1,2, Sirintra Nakjang3, Fadhel Lafta4,5, Kateryna Bilotkach4, Laura Woodhouse6, Gesa Junge3, Susan J Tudhope3, Jonathan P Wallis7, Helen Marr7, Scott Marshall8, Nick Bown9, Elaine Willmore3, Gordon Strathdee10. 1. Newcastle University Centre for Cancer, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. timothy.barrow@sunderland.ac.uk. 2. Faculty of Health Sciences & Wellbeing, University of Sunderland, Sunderland, UK. timothy.barrow@sunderland.ac.uk. 3. Cancer Research UK Drug Discovery Unit, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. 4. Newcastle University Centre for Cancer, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. 5. Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq. 6. School of Medical Education, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. 7. Department of Haematology, Freeman Hospital, Newcastle upon Tyne, UK. 8. Department of Haematology City Hospitals Sunderland NHS Trust, Sunderland Royal Hospital, Sunderland, UK. 9. Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, UK. 10. Newcastle University Centre for Cancer, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. gordon.strathdee@newcastle.ac.uk.
Abstract
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.
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.
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Authors: Maria Tsagiopoulou; Nikos Papakonstantinou; Theodoros Moysiadis; Larry Mansouri; Viktor Ljungström; Martí Duran-Ferrer; Andigoni Malousi; Ana C Queirós; Karla Plevova; Sujata Bhoi; Panagoula Kollia; David Oscier; Achilles Anagnostopoulos; Livio Trentin; Matthias Ritgen; Sarka Pospisilova; Niki Stavroyianni; Paolo Ghia; Jose I Martin-Subero; Christiane Pott; Richard Rosenquist; Kostas Stamatopoulos Journal: Clin Epigenetics Date: 2019-12-02 Impact factor: 6.551
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