Abstract
Multiple myeloma (MM) is a clonal plasma cell malignancy that develops primarily in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, growth, and drug resistance. MM cells furthermore reshape the BM to their own needs by affecting the different BM stromal cell types resulting in angiogenesis, bone destruction, and immune suppression. Despite recent advances in treatment modalities, MM remains most often incurable due to the development of drug resistance to all standard of care agents. This underscores the unmet need for these heavily treated relapsed/refractory patients. Disruptions in epigenetic regulation are a well-known hallmark of cancer cells, contributing to both cancer onset and progression. In MM, sequencing and gene expression profiling studies have also identified numerous epigenetic defects, including locus-specific DNA hypermethylation of cancer-related and B cell specific genes, genome-wide DNA hypomethylation and genetic defects, copy number variations and/or abnormal expression patterns of various chromatin modifying enzymes. Importantly, these so-called epimutations contribute to genomic instability, disease progression, and a worse outcome. Moreover, the frequency of mutations observed in genes encoding for histone methyltransferases and DNA methylation modifiers increases following treatment, indicating a role in the emergence of drug resistance. In support of this, accumulating evidence also suggest a role for the epigenetic machinery in MM cell plasticity, driving the differentiation of the malignant cells to a less mature and drug resistant state. This review discusses the current state of knowledge on the role of epigenetics in MM, with a focus on deregulated histone methylation modifiers and the impact on MM cell plasticity and drug resistance. We also provide insight into the potential of epigenetic modulating agents to enhance clinical drug responses and avoid disease relapse.
Highlights
Multiple myeloma (MM) is a plasma cell (PC) malignancy that mainly resides in the bone marrow (BM)
Cancer is typically considered a genetic disease, multiple lines of evidence have shown that defects in the epigenetic machinery are as important in cancer onset and progression
Epigenetic lesions have been proposed to contribute to many classical hallmarks of cancer, including but not limited to genomic instability, sustained proliferation, invasion and metastasis, evading the immune system and metabolic dysregulation, and might even be considered as a new, additional cancer hallmark
Summary
Multiple myeloma (MM) is a plasma cell (PC) malignancy that mainly resides in the bone marrow (BM). The most frequent translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32); the former dysregulates the CCND1 gene and the latter upregulates FGFR3 (fibroblast growth factor receptor 3) and MMSET genes To these primary events, MM is characterized by secondary events which occur during disease progression and lead to the formation of different subclones, adding to the complexity of the disease. Genetic defects in-, and overexpression of several chromatin modifying enzymes have been described in MM These epimutations are often associated with genomic instability, emergence of drug resistance, MM progression and short progression free survival. We review the current state of knowledge on the role of epigenetics in MM, with a focus on the deregulated HMTs and HDMs and their contribution to clonal heterogeneity, plasticity and drug response in MM
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