The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

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.

Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

“…Chromosomal abnormalities—such as copy-number variations, translocations, and mutations—are crucial primary events for MM initiation 7 . Additionally, aberrant epigenetic landscapes such as DNA methylation and histone modifications further contribute to MM disease progression, clonal heterogeneity, cellular plasticity, and drug resistance 8 . Importantly, genetic and epigenetic aberrations have been shown to orchestrally regulate genomic instability and transcriptomic alterations, which contribute to dedifferentiation of malignant cells to a less mature status that can lead to drug resistance and poor disease progression 8 , 9 .…”

Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors

“…To date, it is widely recognized that alterations of the “epigenome” are therapeutically relevant as well as DNA mutations. Indeed, in contrast to DNA mutations, “epimutations” must be actively maintained through DNA replication for their dynamic nature; thus, their functional effects are reversible and, consequently, targetable [8,9].…”

Targeting NF-κB Signaling for Multiple Myeloma

“…Furthermore, MM development is supported by the promoter methylation of the P53 gene, which is sustained by the NF-κB-regulated cytokine interleukin-6 (IL-6) [ 19 ]. Aside from DNA methylation, histone modifications such as acetylation and methylation also significantly alter the epigenetic landscape and drug response of MM [ 20 ]. For instance, overexpression of the histone methyltransferase gene EZH2 that frequently occurs in MM may be induced by hyperactive non-canonical NF-κB signaling [ 21 ].…”