title: Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control.
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.
authors.affiliation: The Institute of Cancer Research, London, UK.|The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: C
authors.identifier: 0000-0002-7190-0028
authors.initials: C
authors.lastname: Pawlyn
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: M D
authors.initials: MD
authors.lastname: Bright
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Buros
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Stein
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Walters
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: L I
authors.initials: LI
authors.lastname: Aronson
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: F
authors.identifier: 0000-0003-3785-6868
authors.initials: F
authors.lastname: Mirabella
authors.affiliation: The Institute of Cancer Research, London, UK.|The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Jones
authors.affiliation: The Institute of Cancer Research, London, UK.|The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: M F
authors.initials: MF
authors.lastname: Kaiser
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Department of Haematology, Newcastle University, Newcastle, UK.
authors.forename: G H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: P L
authors.identifier: 0000-0003-1523-7388
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Workman
authors.affiliation: Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chesi
authors.affiliation: The Institute of Cancer Research, London, UK.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: The Institute of Cancer Research, London, UK.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Davies
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D015415:Biomarkers; D006657:Histones; D012333:RNA, Messenger; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein