title: 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.
abstract: 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.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Prasoon
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alzrigat
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Alba Atienza
authors.initials: AA
authors.lastname: Párraga
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.affiliation: Department of Biological Engineering, Indian Institute of Technology, Gandhinagar, Gujarat, India.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Singh
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine (HERM), Karolinska Institute Huddinge, Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ungerstedt
authors.affiliation: Department of Oncology-Pathology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Österborg
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nilsson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Öberg
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalushkova
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
mesh_terms: D002843:Chromatin / Q000378:metabolism; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D063146:Polycomb-Group Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D008239:Lysine
keywords: EZH2; H3K27me3; Polycomb; UNC1999; multiple myeloma