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Multiple Myeloma: Focus on Molecular and Epigenetic Aspects
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Multiple Myeloma: Focus on Molecular and Epigenetic Aspects

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 30058

Special Issue Editor

Prof. Dr. Bogusław Machaliński

E-Mail Website
Guest Editor
Department of Physiopathology, Hematology, and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
Interests: multiple myeloma research; experimental and clinical hematology; stem cell-based therapies; immunotherapy; angiogenesis; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is a systemic disease caused by the multifocal proliferation of plasma cells capable of producing monoclonal, homogeneous immunoglobulins whose genes have been recombined or somatically hypermutated. The conversion of normal plasmocytes into an expansive myeloma clone occurs as a result of the disturbance of various processes, e.g., damage to the cytokine network, angiogenesis, chromosomal aberrations (e.g., monosomy 13 and 14q32 translocation) and genetic changes involving Ras/p53. The introduction of new drugs for the treatment of multiple myeloma was a significant breakthrough that improved prognosis and lengthened the average survival time of patients. However, significant molecular, including epigenetic, changes can affect both the pathogenesis of the disease and the patient’s response to treatment, leading to the development of resistance to or side effects from treatment such as peripheral neuropathy.

We therefore invite investigators to contribute original research as well as review articles that focus on efforts to understand and elucidate various aspects of advances in the molecular, including epigenetic, field of research underlying the pathobiology of multiple myeloma affecting the survival or proliferation of myeloma cells, responses to antimyeloma drugs, development of resistance and side effects of therapy.

Research in this area may bring us closer to understanding the pathophysiology of multiple myeloma, developing new effective therapies, and transforming myeloma into a curable disease.

Prof. Dr. Bogusław Machaliński
Guest Editor

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Published Papers (6 papers)

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Research

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15 pages, 2551 KiB  
Article
Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma
by Hideki Kosako, Yusuke Yamashita, Shuhei Morita, Sadahiro Iwabuchi, Shinichi Hashimoto, Taka-Aki Matsuoka, Takashi Sonoki and Shinobu Tamura
Int. J. Mol. Sci. 2022, 23(24), 16162; https://doi.org/10.3390/ijms232416162 - 18 Dec 2022
Cited by 3 | Viewed by 2035
Abstract
Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, [...] Read more.
Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic β cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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17 pages, 2215 KiB  
Article
Bortezomib-Induced Epigenetic Alterations in Nerve Cells: Focus on the Mechanisms Contributing to the Peripheral Neuropathy Development
by Karolina Łuczkowska, Dorota Rogińska, Piotr Kulig, Anna Bielikowicz, Bartłomiej Baumert and Bogusław Machaliński
Int. J. Mol. Sci. 2022, 23(5), 2431; https://doi.org/10.3390/ijms23052431 - 23 Feb 2022
Cited by 8 | Viewed by 2675
Abstract
Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy [...] Read more.
Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy (PN) symptoms. Therefore, it is likely that the BiPN mechanisms are based on temporary/reversible changes such as epigenetic alterations. In this study, we examined the effect of treating nerve cells, differentiated from the Lund human mesencephalic (dLUHMES) cell line, with several low-dose BTZ (0.15 nM) applications. We showed a significant decrease in global histone H3 acetylation as well as histone H3 lysine 9 acetylation. Moreover, analysis of the genetic microarray showed changes mainly in epigenetic processes related to chromatin rearrangement, chromatin silencing, and gene silencing. GSEA analysis revealed three interesting signaling pathways (SIRT1, B-WICH and, b-Catenin) that may play a pivotal role in PN development. We also performed an analysis of the miRNA microarray which showed the interactions of miR-6810-5p with the genes MSN, FOXM1, TSPAN9, and SLC1A5, which are directly involved in neuroprotective processes, neuronal differentiation, and signal transduction. The study confirmed the existence of BTZ-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of PN. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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17 pages, 2273 KiB  
Article
A Cancer-Related microRNA Signature Shows Biomarker Utility in Multiple Myeloma
by Aristea-Maria Papanota, Paraskevi Karousi, Christos K. Kontos, Pinelopi I. Artemaki, Christine-Ivy Liacos, Maria-Alexandra Papadimitriou, Tina Bagratuni, Evangelos Eleutherakis-Papaiakovou, Panagiotis Malandrakis, Ioannis Ntanasis-Stathopoulos, Maria Gavriatopoulou, Efstathios Kastritis, Margaritis Avgeris, Meletios-Athanasios Dimopoulos, Andreas Scorilas and Evangelos Terpos
Int. J. Mol. Sci. 2021, 22(23), 13144; https://doi.org/10.3390/ijms222313144 - 5 Dec 2021
Cited by 13 | Viewed by 2995
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs [...] Read more.
Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspirates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyadenylated. Next, first-strand cDNA synthesis was performed using an oligo-dT–adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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25 pages, 2979 KiB  
Article
Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence
by Emilie Logie, Bart Van Puyvelde, Bart Cuypers, Anne Schepers, Herald Berghmans, Jelle Verdonck, Kris Laukens, Lode Godderis, Maarten Dhaenens, Dieter Deforce and Wim Vanden Berghe
Int. J. Mol. Sci. 2021, 22(22), 12234; https://doi.org/10.3390/ijms222212234 - 12 Nov 2021
Cited by 27 | Viewed by 6355
Abstract
Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies [...] Read more.
Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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Review

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18 pages, 666 KiB  
Review
Pathogenesis and Treatment of Myeloma-Related Bone Disease
by Yuh-Ching Gau, Tsung-Jang Yeh, Chin-Mu Hsu, Samuel Yien Hsiao and Hui-Hua Hsiao
Int. J. Mol. Sci. 2022, 23(6), 3112; https://doi.org/10.3390/ijms23063112 - 14 Mar 2022
Cited by 23 | Viewed by 6364
Abstract
Multiple myeloma is a hematologic malignancy of plasma cells that causes bone-destructive lesions and associated skeletal-related events (SREs). The pathogenesis of myeloma-related bone disease (MBD) is the imbalance of the bone-remodeling process, which results from osteoclast activation, osteoblast suppression, and the immunosuppressed bone [...] Read more.
Multiple myeloma is a hematologic malignancy of plasma cells that causes bone-destructive lesions and associated skeletal-related events (SREs). The pathogenesis of myeloma-related bone disease (MBD) is the imbalance of the bone-remodeling process, which results from osteoclast activation, osteoblast suppression, and the immunosuppressed bone marrow microenvironment. Many important signaling cascades, including the RANKL/RANK/OPG axis, Notch signaling, the Wnt/β-Catenin signaling pathways, and signaling molecules, such as DKK-1, sclerostin, osteopontin, activin A, chemokines, and interleukins are involved and play critical roles in MBD. Currently, bisphosphonate and denosumab are the gold standard for MBD prevention and treatment. As the molecular mechanisms of MBD become increasingly well understood, novel agents are being thoroughly explored in both preclinical and clinical settings. Herein, we will provide an updated overview of the pathogenesis of MBD, summarize the clinical management and guidelines, and discuss novel bone-modifying therapies for further management of MBD. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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18 pages, 695 KiB  
Review
Multiple Myeloma: Challenges Encountered and Future Options for Better Treatment
by Srijit Das, Norsham Juliana, Noor Anisah Abu Yazit, Sahar Azmani and Izuddin Fahmy Abu
Int. J. Mol. Sci. 2022, 23(3), 1649; https://doi.org/10.3390/ijms23031649 - 31 Jan 2022
Cited by 26 | Viewed by 8521
Abstract
Multiple myeloma (MM) is a malignant hematological disease. The disease is characterized by the clonal proliferation of malignant plasma cells in the bone marrow. MM accounts for 1.3% of all malignancies and has been increasing in incidence all over the world. Various genetic [...] Read more.
Multiple myeloma (MM) is a malignant hematological disease. The disease is characterized by the clonal proliferation of malignant plasma cells in the bone marrow. MM accounts for 1.3% of all malignancies and has been increasing in incidence all over the world. Various genetic abnormalities, mutations, and translocation, including epigenetic modifications, are known to contribute to the disease’s pathophysiology. The prognosis is good if detected early, or else the outcome is very bad if distant metastasis has already occurred. Conventional treatment with drugs poses a challenge when there is drug resistance. In the present review, we discuss multiple myeloma and its treatment, drug resistance, the molecular basis of epigenetic regulation, the role of natural products in epigenetic regulators, diet, physical activity, addiction, and environmental pollutants, which may be beneficial for clinicians and researchers. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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