Abstract
Simple SummaryDespite advances made in the last two decades, multiple myeloma (MM) is still an incurable disease. The genetic complexity of MM and the presence of intra-clonal heterogeneity are major contributors to disease relapse and the development of treatment resistance. Additionally, the bone marrow microenvironment is known to play a pivotal role in MM disease progression. Together with genetic modifications, epigenetic changes have been shown to influence MM development and progression. However, epigenetic treatments for MM are still lacking. This is mainly due to the high rate of adverse events of epigenetic drugs in clinical practice. In this review, we will focus on the role of epigenetic modifications in MM disease progression and the development of drug resistance, as well as their role in shaping the interplay between bone marrow stromal cells and MM cells. The current and future treatment strategies involving epigenetic drugs will also be addressed.Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.
Highlights
Clinic of Internal Medicine C, Hematology and Oncology, Stem Cell Transplantation and Palliative Care, Greifswald University Medicine, 17475 Greifswald, Germany
Chapman et al reported an overexpression of HOXA9 both in MM cell lines and in primary patient samples [79], Garcia-Gomez and colleagues demonstrated an increase of HOXA4 but a decrease in HOXA9 in mesenchymal stromal cells derived from MM patients [80]
Research has revealed various dysregulations of the epigenome in MM, only one epigenetic treatment has been approved for this disease so far
Summary
MM is defined by its clonal diversity, which complicates the application of genetically targeted therapy [28]. Genetic modifications but, changes in the epigenome correlate with cancer development [29,30]. DNA methylation is defined by the addition of a methyl group to the carbon-5 position of a cytosine in a cytosine-phosphate-guanine dinucleotide (CpG) and is traditionally associated with gene repression [32]. As many other processes in cell homeostasis, DNA methylation is not an irreversible event but, rather, a dynamic process [32,33]. Whole-exome analysis revealed DNA methylation modifiers, such as TET1/2/3, IDH1/2 and DNMT1/3A/B, to be frequently altered [34]. MM is characterized by global hypomethylation and gene-specific hypermethylation
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