The Role of Epigenetics in the Development and Progression of Multiple Myeloma

Abstract

Multiple myeloma (MM) is an exceptionally complicated and heterogeneous disease that is caused by the abnormal proliferation of malignant monoclonal plasma cells initiated in the bone marrow. In disease progression, a multistep process including differentiation, proliferation, and invasion is involved. Despite great improvement in treatment outcomes in recent years due to the substantial discovery of novel therapeutic drugs, MM is still regarded as an incurable disease. Patients with MM are afflicted by confronting remission periods accompanied by relapse or progression outcomes, which inevitably progress to the refractory stage. In this regard, MM may need new medications or modifications in therapeutic strategies to overcome resistance. A variety of genetic abnormalities (e.g., point mutations, translocations, and deletions) and epigenetic changes (e.g., DNA methylation, histone modification, and non-coding RNA) contribute to the pathogenesis and development of MM. Here, we review the significant roles of epigenetic mechanisms in the development and progression of MM. We also highlight epigenetic pathways as potential novel treatment avenues for MM, including their interplay, use of epigenetic inhibitors, and major involvement in immuno-oncology.

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

“…Interestingly, genes upregulated at the MGUS stage of the MIcγ1 model mirrored those elevated at the MM stage in the BIcγ1 model, supporting the rapid disease progression in the MIcγ1 model (Figure S6B). Likewise, we observed an increased vascular phenotype during the MGUS stage, along with the upregulation of Anxa2, Anxa5, S100a6, and S100a10 in MM genes associated with a more aggressive disease 24,25 (Figures S6C-F).…”

“…Interestingly, genes upregulated in MGUS-MIcγ1 EC mirrored those elevated in MM-BIcγ1 EC, showing an increased vascular phenotype and supporting the rapid disease progression of the MIcγ1 model (supplemental Figure 6B). Likewise, Anxa2, Anxa5, S100a6, and S100a10 were upregulated in MM-MIcγ1 EC, which have been associated with a more aggressive disease 24,25 (Figures S6C-F).…”

Noncoding RNAs and programmed cell death in hepatocellular carcinoma: Significant role of epigenetic modifications in prognosis, chemoresistance, and tumor recurrence rate

“…NcRNAs are assorted into four main kinds, comprising long ncRNA (lncRNA), miRNAs, circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs) (Su & Han, 2023; Zhang, Wang, et al, 2023; Zhang, Xu, et al, 2023). LncRNAs have essential roles in the progression of cancer by RNA editing, degradation, and splicing, translational regulation, regulation of chromatin remodeling, miRNA sponges, and transcription (Ismail et al, 2023). Some lncRNAs, like PVT1, HOTTIP, HOTAIR, and CCAT1, are related to the tumorigenesis and proliferation of thyroid and cervical cancer cells (Cao et al, 2021).…”

Lysin (K)-Specific Demethylase 1 Inhibition Enhances Proteasome Inhibitor Response and Overcomes Drug Resistance in Multiple Myeloma

“…Despite the genetic nature of the disease, it is increasingly recognized that epigenetic machinery plays a crucial role in MM, contributing to the high plasticity of myeloma cells and the development of therapy resistance [12][13][14]. Recent ndings have revealed transcriptional and epigenetic mechanisms of drug resistance that may lead to the emergence of reversible drug-tolerant cells [15][16][17]. Accordingly, several histone modi cation and chromatin remodeling factors, such as Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2), Lysine Demethylase 5 and 6 (KDM5, KDM6), and Histone Deacetylases (HDACs) have been demonstrated to be tolerance-related genes, deregulated in cancer cells after therapeutic regimens [15,[18][19][20].…”

“…Recent ndings have revealed transcriptional and epigenetic mechanisms of drug resistance that may lead to the emergence of reversible drug-tolerant cells [15][16][17]. Accordingly, several histone modi cation and chromatin remodeling factors, such as Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2), Lysine Demethylase 5 and 6 (KDM5, KDM6), and Histone Deacetylases (HDACs) have been demonstrated to be tolerance-related genes, deregulated in cancer cells after therapeutic regimens [15,[18][19][20]. Accordingly, refractory disease can be reversed by epigenetic reprogramming, exploiting combination and intermittent therapies.…”