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The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells

Myelodysplastic syndromes (MDS) are a heterogeneous, clonal haematopoietic disorder, with ~1/3 of patients progressing to acute myeloid leukaemia (AML). Many elderly MDS patients do not tolerate intensive therapeutic regimens, and therefore have an unmet need for better tolerated therapies. Epigenet...

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Autores principales: Clarke, Kathryn, Young, Christine, Liberante, Fabio, McMullin, Mary-Frances, Thompson, Alexander, Mills, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544403/
https://www.ncbi.nlm.nih.gov/pubmed/31191819
http://dx.doi.org/10.18632/oncotarget.26877
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author Clarke, Kathryn
Young, Christine
Liberante, Fabio
McMullin, Mary-Frances
Thompson, Alexander
Mills, Ken
author_facet Clarke, Kathryn
Young, Christine
Liberante, Fabio
McMullin, Mary-Frances
Thompson, Alexander
Mills, Ken
author_sort Clarke, Kathryn
collection PubMed
description Myelodysplastic syndromes (MDS) are a heterogeneous, clonal haematopoietic disorder, with ~1/3 of patients progressing to acute myeloid leukaemia (AML). Many elderly MDS patients do not tolerate intensive therapeutic regimens, and therefore have an unmet need for better tolerated therapies. Epigenetics is important in the pathogenesis of MDS/AML with DNA methylation, and histone acetylation the most widely studied modifications. Epigenetic therapeutic agents have targeted the reversible nature of these modifications with some clinical success. The aim of this study was to characterise the molecular consequences of treatment of MDS and AML cells with the histone deacetylase inhibitor (HDACi) Romidepsin. Romidepsin as a single agent induced cell death with an increasing dose and time profile associated with increased acetylation of histone H3 lysine 9 (H3K9) and decreased HDAC activity. Gene expression profiling, qPCR, network and pathway analysis recognised that oxidation-reduction was involved in response to Romidepsin. ROS was implicated as being involved post-treatment with the involvement of TSPO and MPO. Genomic analysis uncoupled the differences in protein-DNA interactions and gene regulation. The spatial and temporal transcriptional differences associated with acetylated, mono- and tri-methylated H3K9, representative of two activation and a repression mark respectively, were identified. Bioinformatic analysis uncovered positional enrichment and transcriptional differences between these marks; a degree of overlap with increased/decreased gene expression that correlates to increased/decreased histone modification. Overall, this study has unveiled a number of underlying mechanisms of the HDACi Romidepsin that could identify potential drug combinations for use in the clinic.
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spelling pubmed-65444032019-06-12 The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells Clarke, Kathryn Young, Christine Liberante, Fabio McMullin, Mary-Frances Thompson, Alexander Mills, Ken Oncotarget Research Paper Myelodysplastic syndromes (MDS) are a heterogeneous, clonal haematopoietic disorder, with ~1/3 of patients progressing to acute myeloid leukaemia (AML). Many elderly MDS patients do not tolerate intensive therapeutic regimens, and therefore have an unmet need for better tolerated therapies. Epigenetics is important in the pathogenesis of MDS/AML with DNA methylation, and histone acetylation the most widely studied modifications. Epigenetic therapeutic agents have targeted the reversible nature of these modifications with some clinical success. The aim of this study was to characterise the molecular consequences of treatment of MDS and AML cells with the histone deacetylase inhibitor (HDACi) Romidepsin. Romidepsin as a single agent induced cell death with an increasing dose and time profile associated with increased acetylation of histone H3 lysine 9 (H3K9) and decreased HDAC activity. Gene expression profiling, qPCR, network and pathway analysis recognised that oxidation-reduction was involved in response to Romidepsin. ROS was implicated as being involved post-treatment with the involvement of TSPO and MPO. Genomic analysis uncoupled the differences in protein-DNA interactions and gene regulation. The spatial and temporal transcriptional differences associated with acetylated, mono- and tri-methylated H3K9, representative of two activation and a repression mark respectively, were identified. Bioinformatic analysis uncovered positional enrichment and transcriptional differences between these marks; a degree of overlap with increased/decreased gene expression that correlates to increased/decreased histone modification. Overall, this study has unveiled a number of underlying mechanisms of the HDACi Romidepsin that could identify potential drug combinations for use in the clinic. Impact Journals LLC 2019-05-28 /pmc/articles/PMC6544403/ /pubmed/31191819 http://dx.doi.org/10.18632/oncotarget.26877 Text en Copyright: © 2019 Clarke et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Clarke, Kathryn
Young, Christine
Liberante, Fabio
McMullin, Mary-Frances
Thompson, Alexander
Mills, Ken
The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells
title The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells
title_full The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells
title_fullStr The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells
title_full_unstemmed The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells
title_short The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells
title_sort histone deacetylase inhibitor romidepsin induces as a cascade of differential gene expression and altered histone h3k9 marks in myeloid leukaemia cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544403/
https://www.ncbi.nlm.nih.gov/pubmed/31191819
http://dx.doi.org/10.18632/oncotarget.26877
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