Targeting Epigenetic Mechanisms in Multiple Myeloma: Comparison
Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Ali Mussa.

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.

  • multiple myeloma
  • DNA methylation
  • histone modification

1. Targeting DNA Methylation

Between the years 2004 and 2015, the United States Food and Drug Administration (FDA) granted authorisation for the use of six different epigenetic agents in clinical trials. These epigenetic agents include azacytidine, 5-aza-2′-deoxycytidine, suberoylanilide hydroxamic acid (SAHA), romidepsin, belinostat, panobinostat and chidamide [112][1]. In addition, the FDA has granted approval for the therapeutic use of 5-aza-2′deoxycytidine (5-aza-AZA; decitabine) and 5-aza-acytidine (5-aza-AZA) for the treatment of patients who suffer from MDS and chronic myelomonocytic leukaemia. These two epigenetic drugs did not have a clinical license to treat myelodysplastic syndromes [113][2], but they did display anti-myeloma efficacy in vitro and in vivo [114,115][3][4]. AZA [116][5] and DAC [117][6] accelerate clonal cell cycle arrest by boosting the activation of negative cell cycle regulators, which ultimately leads to apoptosis and senescence pathways (p16 and p15). G0/G1 and G2/M cell cycle arrests involving p21 and p38 were detected following DAC therapy [117][6]. Curiously, AZA in combination with doxorubicin and bortezomib had synergistic anti-MM efficacy [118][7] and restored sensitivity to dexamethasone [119][8]. Both AZA and 5-aza-2′-deoxycytidine (DAC) are capable of exerting detrimental effects by integrating into DNA and blocking covalently bound DNMT enzymes, which in turn causes DNMT damage and passive DNA demethylation [120][9]. In a model of murine myeloma, treatment with CM-272, an inhibitor combination that blocks both DNMTs and the histone methyltransferase G9a, decreases bone loss associated with the tumour and reduces the overall volume of the tumour. Utilising inhibitors allows for the induction of osteoblast formation in myeloma MSCs and the restoration of the expression of hypermethylated osteogenic regulators [46][10].

2. Targeting Histone Acetylation

HDACi displays anti-MM activity in cells by activating the apoptotic pathway, inhibiting the proteasome, and decreasing tumorigenesis and treatment resistance [121,122][11][12]. WT161, an HDAC6 inhibitor, induces cell death by boosting tubulin acetylation and inhibiting aggresome-dependent protein degradation in MM cells both in vitro and in vivo [123][13]. Panobinostat (LBH589) is a pan-HDACi that interacts with bortezomib and has been licensed for patients with relapsed or refractory MM [124][14] due to its ability to inhibit class I, II, and IV HDACs at a low nanomolar concentration [125,126][15][16]. This agent inhibits aggresome and proteasome networks and enhances the acetylation of proteins implicated in many carcinogenic pathways in MM cells [127][17]. Thus, progression-free survival (PFS) and complete and near-complete responses were significantly enhanced. Nevertheless, some individuals had adverse symptoms, including thrombocytopenia, diarrhoea, asthenia, and weariness. The combined treatment of panobinostat, bortezomib, and dexamethasone is predicted to benefit patients with MM cancer who developed bortezomib resistance [128][18]. Additionally, the first oral selective HDAC6 inhibitor, Ricolinostat (ACY-1215), showed reduced class I HDAC activity when coupled with carfilzomib [129][19], lenalidomide, and dexamethasone [130][20], showing anti-MM effects following therapy. HDACi concentrates on bromodomain and the extra-terminal domain (BET) because the BET proteins physically link the enhancer and promoter regions to stimulate the initiation and extension of gene transcription. By blocking the MYC oncogene and its gene expression network, BET inhibitors have shown an anti-MM effect in vitro and/or in vivo, either alone or in combination, highlighting that BET inhibitors might be considered a feasible therapeutic intervention in MM [131][21].

3. Targeting Histone Methylation

Inhibitors of histone methyltransferase for enhancer of zeste homolog 2 (EZH2) are emerging as an epigenetic therapy strategy for MM disease whether used alone or in combination with other targeted drugs. EZH2, which contains the enzyme component of the polycomb repressive complex 2 (PRC2), is essential for both normal cell development and the progression of disease (PRC2). PRC2 in EZH2 catalyses the methylation of histone H3 lysine tail residue 27 (H3K27me3), which induces the reprogramming of cells associated with stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. Thus, the discovery of highly selective inhibitors of EZH2’s histone methyltransferase activity has shed light on the function of EZH2 and PRC2 in carcinogenesis and their potential as cancer therapy targets [77][22].
Since both target combinations allow for the control of gene expression, histone H3 lysine 27 (H3K27) methyltransferase and G9, an H3K9 methyltransferase, have been identified as another promising therapeutic target in MM. To be more specific, the combination of these two inhibitors induces cell cycle arrest and triggers the pathway that leads to apoptosis, which in turn lowers the rate of MM cell growth. In addition, an examination in animals demonstrated an anticancer effect, as shown by a decrease in the formation of MM cell xenografts. There is also a correlation between greater levels of EZH2 and EHMT2 expression (both of which encode G9a) and worse outcomes for patients with MM. In contrast, the inhibition of EZH2/G9a resulted in an increase in the expression of genes that are activated by IFN and a reduction in the expression of genes that are involved in the IRF4-MYC axis in MM cells. This is supported by the observation that the degree of ERV gene expression in MM cells has dramatically risen and that the H3K27/H3K9 methylation levels have decreased, both of which are indicators of an IFN response [132][23].
The methylation process in histone H3 lysine-4 (H3K4), -36 (H3K36), and -79 (H3K79) caused transcriptional pathway upregulation in MM cells. Gene silencing events, on the other hand, were shown by methylation involving histone H4 lysine 20 (H4K20) [133][24]. For instance, GSK126, the EZH2 inhibitor, has been administrated to patients with MM with relapsed or refractory phases in phase I clinical trials [134][25]. Furthermore, MMSET histone methyltransferase was discovered as a promising target for epigenetic treatment in MM due to the anti-tumour activity shown following the shRNA-mediated suppression of MM cells in vitro and in vivo [135][26]. Consequently, LEM-06 has been introduced as an MMSET inhibitor to serve as an alternative model for assessing the therapeutic potential of MMSET in MM [136][27].
Table 21 outlines the types of epigenetic inhibitors administered to patients with MM, along with their mode of action.
Table 21.
The types of epigenetic inhibitors administered to patients with MM.


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