There 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.
Multiple myeloma (MM), epigenetics, DNA methylation, histone modifications, histone deacetylases inhibitors, panobinostat, ricolinostat, combination strategies
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.
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.
Medical writing assistance was provided by Catherine Amey at Touch Medical Media, UK, supported by Novartis.
August 03, 2016 Accepted
September 20, 2016
Andrew Spencer, Alfred Health, 55 Commercial Road, Melbourne, Victoria 3004, Australia. E: firstname.lastname@example.org
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.
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.
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 malignancy6 and accounts for approximately 20% of deaths from haematological malignancies7 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).12Over 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, which is the best characterised epigenetic modification, occurs in cytosinecontaining 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 phenotype (CIMP), was first identified in colorectal cancer24 and has been observed extensively in a wide variety of tumours,25 although CIMP has rarely been reported in MM.26 MM is however characterised by a level of heterogeneity in DNA methylation that exceeds that described in several solid cancers.27,28
The DNA methylome, which is the map of DNA methylation modifications, has been described in normal plasma cells (NPCs) and plasma cells from MGUS and MM patient samples (Figure 1).29 Aberrant methylation patterns are related to disease stage in MM with significant difference and heterogeneity in the global methylation patterns in the malignant cell types (MM, primary plasma cell leukaemia and in human myeloma cell lines) compared to the non-malignant cells (non-plasma cell disorders and MGUS).17 DNA methylation at transcription start sites and gene promoters has been associated with the formation of heterochromatin and long-term gene silencing.30,31 Methylation is also an inactivating mechanism of the tumour suppressor p16 gene in MM, which is associated with high plasma cell proliferation and short survival.32 Furthermore, p16 methylation may be a marker for overall epigenetic changes associated with disease progression.33 Global methylation analysis in MM has pinpointed inactivated tumour suppressor genes that are prognostically important.28 In an analysis of the association of differential DNA methylation with prognosis in 159 patients with myeloma, 195 genes with changes in DNA methylation were identified. Hypermethylation of the genes GPX3, RBP1, SPARC and TGFBI was associated with significantly shorter overall survival (OS); this association was independent of age, International Staging System score, and adverse cytogenetics.28
The most comprehensive methylation study to date has demonstrated that B-cell specific intronic enhancers undergo DNA hyper-methylation, resulting in enhanced decommissioning of genes related to B-cell differentiation consistent with MM acquiring or preserving a ‘stem cell-like’ methylome.30 Finally, the expression of DNA (cytosine-5-)- methyltransferase 1 (DNMT1) is also known to be upregulated during disease pathogenesis compared to NPCs and silencing of DNMT1 significantly reduced the methylation of p16.34,35
MicroRNA are a class of short non-coding RNA molecules with RNA silencing functions.36 Epigenetic dysregulation of tumour-suppressor microRNA genes via DNA methylation has also been implicated in MM.37
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Multiple myeloma (MM), epigenetics, DNA methylation, histone modifications, histone deacetylases inhibitors, panobinostat, ricolinostat, combination strategies