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Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Gyllensten)ORCID iD: 0000-0002-5056-9137
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, 6809-6923 p.Article in journal (Refereed) Published
Abstract [en]

Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

Place, publisher, year, edition, pages
2016. Vol. 7, no 6, 6809-6923 p.
Keyword [en]
multiple myeloma; Polycomb; EZH2; H3K27me3; UNC1999
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-289186DOI: 10.18632/oncotarget.6843ISI: 000376123100032PubMedID: 26755663OAI: oai:DiVA.org:uu-289186DiVA: diva2:924812
Funder
Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), R01GM103893
Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2016-07-01Bibliographically approved

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Alzrigat, MohammadPárraga, Alba AtienzaEnroth, StefanNilsson, KennethÖberg, FredrikKalushkova, AntoniaJernberg-Wiklund, Helena
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Experimental and Clinical OncologyDepartment of Immunology, Genetics and PathologyInfectious Diseases
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