Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control.
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Date
2017-03-31Author
Pawlyn, C
Bright, MD
Buros, AF
Stein, CK
Walters, Z
Aronson, LI
Mirabella, F
Jones, JR
Kaiser, MF
Walker, BA
Jackson, GH
Clarke, PA
Bergsagel, PL
Workman, P
Chesi, M
Morgan, GJ
Davies, FE
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Cell Line, Tumor
Mesenchymal Stem Cells
Humans
Multiple Myeloma
Histones
RNA, Messenger
Prognosis
Proportional Hazards Models
Gene Expression Profiling
Apoptosis
Cell Proliferation
Cell Survival
Gene Expression
Epigenesis, Genetic
Phenotype
Kaplan-Meier Estimate
Cell Cycle Checkpoints
Biomarkers
Enhancer of Zeste Homolog 2 Protein
Research team
Myeloma Biology and Therapeutics
Signal Transduction & Molecular Pharmacology
Myeloma Group
Sarcoma Molecular Pathology
Language
eng
Date accepted
2017-02-23
License start date
2017-03-31
Citation
Blood cancer journal, 2017, 7 (3), pp. e549 - ?
Publisher
SPRINGERNATURE