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Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries. It has recently been shown that the homogeneity of the chromatin landscape between CLL cells contrasts with the important observed genetic heterogeneity of the disease. To gain further insight into the consequence...

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Autores principales: Holmes, Katie B., Sadreev, Ildar I., Rawstron, Andy C., Munir, Tal, Westhead, David R., Hillmen, Peter, Lefevre, Pascal F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510766/
https://www.ncbi.nlm.nih.gov/pubmed/31076570
http://dx.doi.org/10.1038/s41389-019-0142-2
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author Holmes, Katie B.
Sadreev, Ildar I.
Rawstron, Andy C.
Munir, Tal
Westhead, David R.
Hillmen, Peter
Lefevre, Pascal F.
author_facet Holmes, Katie B.
Sadreev, Ildar I.
Rawstron, Andy C.
Munir, Tal
Westhead, David R.
Hillmen, Peter
Lefevre, Pascal F.
author_sort Holmes, Katie B.
collection PubMed
description Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries. It has recently been shown that the homogeneity of the chromatin landscape between CLL cells contrasts with the important observed genetic heterogeneity of the disease. To gain further insight into the consequences of disease evolution on the epigenome’s plasticity, we monitored changes in chromatin structure occurring in vivo in CLL cells from patients receiving continuous Ibrutinib treatment. Ibrutinib, an oral inhibitor of the Bruton’s tyrosine kinase (BTK) has proved to be remarkably efficient against treatment naïve (TN), heavily pre-treated and high-risk chronic lymphocytic leukaemia (CLL), with limited adverse events. We established that the chromatin landscape is significantly and globally affected in response to Ibrutinib. However, we observed that prior to treatment, CLL cells show qualitative and quantitative variations in chromatin structure correlated with both EZH2 protein level and cellular response to external stimuli. Then, under prolonged exposure to Ibrutinib, a loss of the two marks associated with lysine 27 (acetylation and trimethylation) was observed. Altogether, these data indicate that the epigenome of CLL cells from the peripheral blood change dynamically in response to stimuli and suggest that these cells might adapt to the Ibrutinib “hit” in a process leading toward a possible reduced sensitivity to treatment.
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spelling pubmed-65107662019-07-05 Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells Holmes, Katie B. Sadreev, Ildar I. Rawstron, Andy C. Munir, Tal Westhead, David R. Hillmen, Peter Lefevre, Pascal F. Oncogenesis Article Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries. It has recently been shown that the homogeneity of the chromatin landscape between CLL cells contrasts with the important observed genetic heterogeneity of the disease. To gain further insight into the consequences of disease evolution on the epigenome’s plasticity, we monitored changes in chromatin structure occurring in vivo in CLL cells from patients receiving continuous Ibrutinib treatment. Ibrutinib, an oral inhibitor of the Bruton’s tyrosine kinase (BTK) has proved to be remarkably efficient against treatment naïve (TN), heavily pre-treated and high-risk chronic lymphocytic leukaemia (CLL), with limited adverse events. We established that the chromatin landscape is significantly and globally affected in response to Ibrutinib. However, we observed that prior to treatment, CLL cells show qualitative and quantitative variations in chromatin structure correlated with both EZH2 protein level and cellular response to external stimuli. Then, under prolonged exposure to Ibrutinib, a loss of the two marks associated with lysine 27 (acetylation and trimethylation) was observed. Altogether, these data indicate that the epigenome of CLL cells from the peripheral blood change dynamically in response to stimuli and suggest that these cells might adapt to the Ibrutinib “hit” in a process leading toward a possible reduced sensitivity to treatment. Nature Publishing Group UK 2019-05-10 /pmc/articles/PMC6510766/ /pubmed/31076570 http://dx.doi.org/10.1038/s41389-019-0142-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Holmes, Katie B.
Sadreev, Ildar I.
Rawstron, Andy C.
Munir, Tal
Westhead, David R.
Hillmen, Peter
Lefevre, Pascal F.
Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
title Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
title_full Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
title_fullStr Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
title_full_unstemmed Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
title_short Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
title_sort ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510766/
https://www.ncbi.nlm.nih.gov/pubmed/31076570
http://dx.doi.org/10.1038/s41389-019-0142-2
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