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

Lookup NU author(s): Dr Timothy Barrow, Dr Sirintra Nakjang, Kateryna Bilotkach, Dr Laura Woodhouse, Gesa Junge, Dr Susan Tudhope, Dr Jonathan Wallis, Dr Helen Marr, Dr Scott Marshall, Dr Nicholas Bown, Dr Elaine Willmore, Dr Gordon Strathdee

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Springer Nature, 2020.

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Abstract

© 2020, The Author(s), under exclusive licence to Cancer Research UK.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.


Publication metadata

Author(s): Barrow TM, Nakjang S, Lafta F, Bilotkach K, Woodhouse L, Junge G, Tudhope SJ, Wallis JP, Marr H, Marshall S, Bown N, Willmore E, Strathdee G

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2020

Volume: 124

Pages: 474-483

Print publication date: 19/01/2021

Online publication date: 21/10/2020

Acceptance date: 25/09/2020

Date deposited: 30/10/2020

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41416-020-01117-8

DOI: 10.1038/s41416-020-01117-8


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