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
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Prasoon Agarwal1,*, Mohammad Alzrigat1,*, Alba Atienza Párraga1, Stefan Enroth1, Umashankar Singh2, Johanna Ungerstedt3, Anders Österborg4, Peter J. Brown5, Anqi Ma6, Jian Jin6, Kenneth Nilsson1, Fredrik Öberg1, Antonia Kalushkova1,‡, Helena Jernberg-Wiklund1,‡
1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
2Department of Biological Engineering, Indian Institute of Technology, Gandhinagar, Gujarat, India
3Department of Medicine, Center for Hematology and Regenerative Medicine (HERM), Karolinska Institute Huddinge, Stockholm, Sweden
4Department of Oncology-Pathology, Karolinska University Hospital Solna, Stockholm, Sweden
5Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
6Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
*These authors have contributed equally to this work
‡Corresponding last co-authors
Helena Jernberg-Wiklund, e-mail: [email protected]
Antonia Kalushkova, e-mail: [email protected]
Keywords: multiple myeloma, Polycomb, EZH2, H3K27me3, UNC1999
Received: June 03, 2015 Accepted: December 29, 2015 Published: January 7, 2016
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.
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