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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

Clarke, Kathryn; Young, Christine; Liberante, Fabio; McMullin, Mary Frances; Thompson, Alexander; Mills, Ken

Authors

Kathryn Clarke

Christine Young

Fabio Liberante

Mary Frances McMullin

Ken Mills



Abstract

© 2020 Ivyspring International Publisher. All rights reserved. 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.

Citation

Clarke, K., Young, C., Liberante, F., McMullin, M. F., Thompson, A., & Mills, K. (2019). The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells. Oncotarget, 10(37), 3462-3471. https://doi.org/10.18632/oncotarget.26877

Journal Article Type Article
Acceptance Date Apr 3, 2019
Online Publication Date May 28, 2019
Publication Date May 1, 2019
Deposit Date Jul 15, 2019
Publicly Available Date Mar 29, 2024
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 10
Issue 37
Pages 3462-3471
DOI https://doi.org/10.18632/oncotarget.26877
Keywords Oncology
Public URL https://nottingham-repository.worktribe.com/output/2307037
Publisher URL http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26877&path[]=85040

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