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.

Prasoon Agarwal,Anders Österborg,Johanna Ungerstedt,Peter J Brown,Fredrik Öberg,Anqi Ma,Alba Atienza Párraga,Jian Jin,Umashankar Singh,Stefan Enroth,Kenneth Nilsson,Helena Jernberg-Wiklund,Mohammad Alzrigat,Antonia Kalushkova

doi:10.18632/oncotarget.6843

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.

Highlights

Multiple myeloma (MM) is a plasma cell tumor localized to the bone marrow
Using an integrative genomic approach, we recently provided proof-of-principle that gene silencing associated with H3K27me3 was increased in malignant MM cells compared to their normal counterparts [15]
We have previously identified Polycomb gene targeting as a common denominator of underexpressed genes in the malignant plasma cell [15]

Summary

Introduction

Multiple myeloma (MM) is a plasma cell tumor localized to the bone marrow. The disease is further characterized by lytic bone lesions and immunodeficiency associated with monoclonal protein in the blood and/ or urine [1, 2]. The t(4;14) translocation highlights the importance of epigenetic modulators in MM, as the multiple myeloma SET domain (MMSET) is known to establish dimethylation of histone H3 at lysine 36 (H3K36me2) [11]. In a proportion of primary MM and MM cell lines lacking t(4;14) a recurrent mutation in the H3K27 demethylase KDM6A ( known as UTX) has been reported [14], further highlighting an emerging role of chromatin modifiers in MM. In these cases, epigenetic deregulation has so far only been observed in a subpopulation of patients. In MM, EZH2 has previously been suggested to have oncogenic properties based on its overexpression and correlation of histone methyltransferase activity to tumor formation in vivo [22]

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Conclusion