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

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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.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Divisions: Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences
Depositing User: Timothy Barrow
Date Deposited: 28 Sep 2020 15:18
Last Modified: 25 Mar 2021 03:38
URI: http://sure.sunderland.ac.uk/id/eprint/12635
ORCID for Timothy Barrow: ORCID iD orcid.org/0000-0003-4551-3857

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