To view this page ensure that Adobe Flash Player version 11.1.0 or greater is installed.

Review Multiple Myeloma Epigenetics in the Biology and Treatment of Multiple Myeloma Andrew Spencer 1 and Sridurga Mithraprabhu 2 1. Malignant Haematology & Stem Cell Transplantation Service; 2. Australian Centre for Blood Diseases, Alfred Hospital-Monash University, Melbourne, Australia T here is a critical need for more effective therapies in multiple myeloma (MM) since all patients eventually relapse following front-line treatment. A variety of both genetic and epigenetic abnormalities may be present in MM, the latter including DNA and histone methylation and histone deacetylation, and are thought to contribute to the pathogenesis of the disease. For example, global methylation analysis in MM has identified inactivated tumour suppressor genes that are prognostically important. Through their ability to acetylate histones and cytoplasmic proteins, histone deacetylases (HDAC) influence a wide variety of cellular functions, such as proliferation, differentiation and apoptosis. Increased class 1 HDAC expression has been linked in solid tumours with more locally advanced, de-differentiated and proliferative tumours, and with poor prognosis in MM. HDAC inhibitors, panobinostat and ricolinostat, have been demonstrated to be effective in combination with bortezomib and dexamethasone in newly diagnosed patients with MM and in heavily pre-treated patients with advanced MM. HDAC inhibitor–monoclonal antibody combinations are also being explored. The potential of HDAC inhibitors to improve outcome for patients with MM is evident but a greater understanding of their anti-tumour effects is needed. Keywords Multiple myeloma (MM), epigenetics, DNA methylation, histone modifications, histone deacetylases inhibitors, panobinostat, ricolinostat, combination strategies Disclosure: Andrew Spencer and Sridurga Mithraprabhu have nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Acknowledgements: Medical writing assistance was provided by Catherine Amey at Touch Medical Media, UK, supported by Novartis. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 3 August 2016 Accepted: 20 September 2016 Citation: European Oncology & Haematology, 2016;12(2):96–102 Corresponding Author: Andrew Spencer, Alfred Health, 55 Commercial Road, Melbourne, Victoria 3004, Australia. E: Support: The publication of this article was supported by Novartis. The views and opinions expressed are those of the authors and do not necessarily reflect those of Novartis. The authors provided Novartis with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion. Epigenetics encompasses heritable changes in the pattern of gene expression mediated by mechanisms other than alterations in primary nucleotide sequence. The epigenome is an inheritable record of changes to the DNA and histone proteins, such as methylation and nucleosome remodelling that directs which genes are to be silenced or expressed. Following early studies of abnormal gene expression in cancer, epigenetic modifications have been recognised to be of central importance in cancer pathophysiology. 1 Mutations in regulators of the epigenome have been identified in cancer that have roles such as ‘writers’, ‘readers’, ‘erasers’ or ‘editors’ and have the potential to deregulate the expression of hundreds of genes genome-wide. 2 Multiple myeloma (MM), a clonal expansion of plasma cells, is characterised by monoclonal protein production, end-organ damage and marked clinical and genetic heterogeneity. 3–5 MM is the second most common haematological malignancy 6 and accounts for approximately 20% of deaths from haematological malignancies 7 and 0.8% of deaths from all cancers; 8,9 in addition, MM is associated with high costs in healthcare provision. 10 The median age of MM diagnosis is 74 years. 11 In Europe, between 2005 and 2009, there was an over two-fold difference between the highest male cancer mortality in Hungary (235.2/100 000) and the lowest mortality in Sweden (112.9/100 000), and a 1.7-fold one in women (from 124.4 in Denmark to 71.0/100 000 in Spain). 12 Over the past decade, however, survival of patients with MM has improved dramatically with the advent of newer therapies. 13 MM always follows the premalignant state of monoclonal gammopathy of undetermined significance (MGUS), although the precise molecular mechanisms involved in the progression from MGUS to MM are not properly understood. Various distinct genetic abnormalities have been reported in both MM and MGUS including epigenetic alterations such as DNA and histone methylation, and are known to contribute to the pathogenesis of the disease. 14–17 Front-line treatment of MM can result in high response rates, 18–21 although all patients eventually relapse and more effective therapies are needed. MM is heterogeneous and is associated with complex gene abnormalities and multiple signalling aberrations. A strategy of targeting single signalling pathways, genes or individual gene products may not therefore be inadequate to supress MM cell growth. 22 The aim of this review is to describe epigenetic modifications and therapeutic combination strategies in MM. DNA methylation DNA methylation, which is the best characterised epigenetic modification, occurs in cytosine- containing nucleotides that are immediately followed by nucleotide sequences containing guanine (i.e., cytosine-phosphodiester bond-guanine [CpG] islands). Located in 60% of promoters, CpG islands, when methylated usually results in silencing of tumour suppressor genes. 23 These events are more frequent than tumour suppressor gene mutations. The CpG island methylator 96 TOU C H ME D ICA L ME D IA