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Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia

Barrow, Timothy, Nakjang, Sirintra, Lafta, Fadhel, Bilotkach, Kateryna, Woodhouse, Laura, Junge, Gesa, Tudhope, Susan J, Wallis, Jonathan P, Marr, Helen, Marshall, Scott, Bown, Nick, Willmore, Elaine and Strathdee, Gordon (2020) Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia. British Journal of Cancer, 124. pp. 474-483. ISSN 0007-0920

Item Type: Article


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 time-points 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 were 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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Depositing User: Timothy Barrow


Item ID: 12635
Identification Number:
ISSN: 0007-0920
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ORCID for Timothy Barrow: ORCID iD

Catalogue record

Date Deposited: 28 Sep 2020 15:18
Last Modified: 25 Mar 2021 03:38


Author: Timothy Barrow ORCID iD
Author: Sirintra Nakjang
Author: Fadhel Lafta
Author: Kateryna Bilotkach
Author: Laura Woodhouse
Author: Gesa Junge
Author: Susan J Tudhope
Author: Jonathan P Wallis
Author: Helen Marr
Author: Scott Marshall
Author: Nick Bown
Author: Elaine Willmore
Author: Gordon Strathdee

University Divisions

Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences


Sciences > Biomedical Sciences
Sciences > Health Sciences

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