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Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control

Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control
Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control

Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.

Apoptosis, Biomarkers, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Cell Survival, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression, Gene Expression Profiling, Histones, Humans, Kaplan-Meier Estimate, Mesenchymal Stromal Cells, Multiple Myeloma, Phenotype, Prognosis, Proportional Hazards Models, RNA, Messenger, Journal Article
2044-5385
Pawlyn, C.
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Bright, M.D.
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Buros, A.F.
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Stein, C.K.
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Walters, Z.
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Aronson, L.I.
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Mirabella, F.
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Jones, J.R.
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Kaiser, M.F.
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Walker, B.A.
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Jackson, G.H.
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Clarke, P.A.
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Bergsagel, P.L.
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Workman, P.
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Chesi, M.
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Morgan, G.J.
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Davies, F.E.
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Pawlyn, C.
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Bright, M.D.
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Buros, A.F.
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Stein, C.K.
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Walters, Z.
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Aronson, L.I.
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Mirabella, F.
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Jones, J.R.
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Kaiser, M.F.
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Walker, B.A.
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Jackson, G.H.
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Clarke, P.A.
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Bergsagel, P.L.
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Workman, P.
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Chesi, M.
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Morgan, G.J.
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Davies, F.E.
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Pawlyn, C., Bright, M.D., Buros, A.F., Stein, C.K., Walters, Z., Aronson, L.I., Mirabella, F., Jones, J.R., Kaiser, M.F., Walker, B.A., Jackson, G.H., Clarke, P.A., Bergsagel, P.L., Workman, P., Chesi, M., Morgan, G.J. and Davies, F.E. (2017) Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer Journal, 7 (3), [e549]. (doi:10.1038/bcj.2017.27).

Record type: Article

Abstract

Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.

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Accepted/In Press date: 23 February 2017
e-pub ahead of print date: 31 March 2017
Keywords: Apoptosis, Biomarkers, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Cell Survival, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression, Gene Expression Profiling, Histones, Humans, Kaplan-Meier Estimate, Mesenchymal Stromal Cells, Multiple Myeloma, Phenotype, Prognosis, Proportional Hazards Models, RNA, Messenger, Journal Article

Identifiers

Local EPrints ID: 416358
URI: http://eprints.soton.ac.uk/id/eprint/416358
ISSN: 2044-5385
PURE UUID: c9cef0a7-d9c5-4cab-92d3-21abc59b7352
ORCID for Z. Walters: ORCID iD orcid.org/0000-0002-1835-5868

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Date deposited: 14 Dec 2017 17:30
Last modified: 11 May 2024 01:54

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Contributors

Author: C. Pawlyn
Author: M.D. Bright
Author: A.F. Buros
Author: C.K. Stein
Author: Z. Walters ORCID iD
Author: L.I. Aronson
Author: F. Mirabella
Author: J.R. Jones
Author: M.F. Kaiser
Author: B.A. Walker
Author: G.H. Jackson
Author: P.A. Clarke
Author: P.L. Bergsagel
Author: P. Workman
Author: M. Chesi
Author: G.J. Morgan
Author: F.E. Davies

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