Molecular Insights in Multiple Myeloma Pathogenesis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 July 2021) | Viewed by 20138

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Guest Editor
Associate professor in hematology, Università degli studi Magna Graecia di Catanzaro, Catanzaro, Italy
Interests: multiple myeloma pathogenesis; tumor immunotherapy
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Special Issue Information

Dear Colleagues,

In the last few years, extensive preclinical research has led to impressive progress in the comprehension of the pathogenesis of multiple myeloma (MM). Indeed, the development of cell lines and the possibility to isolate primary malignant plasma cells and surrounding microenvironmental cells from the tumor bed have allowed investigators to apply “omics” assays to dissect the molecular pathways involved in the onset and progression of the disease. Furthermore, the peculiar natural history of MM, arising from asymptomatic stages, has prompted advanced studies of clonal dynamics and evolution which represent the basis of future investigations in other solid and hematological tumors.

The scope of this Special Issue is to collect original contributions from expert researchers in the field of MM molecular biology to outline the state-of-art of preclinical research and future perspectives in this area.

Prof. Dr. Marco Rossi
Guest Editor

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Keywords

  • Malignant plasma cell biology 
  • Multiple myeloma genomics 
  • Clonal evolution in multiple myeloma 
  • Omics technology in multiple myeloma 
  • Malignant plasma cells single cell analysis 
  • Multiple myeloma microenvironment

Published Papers (6 papers)

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Research

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14 pages, 9963 KiB  
Article
The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma
by Nicholas Nikesitch, Patricia Rebeiro, Lye Lin Ho, Srinivasa Pothula, Xin Maggie Wang, Tiffany Khong, Hazel Quek, Andrew Spencer, Cheok Soon Lee, Tara L. Roberts and Silvia C. W. Ling
Cells 2021, 10(12), 3464; https://doi.org/10.3390/cells10123464 - 8 Dec 2021
Cited by 10 | Viewed by 2895
Abstract
Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM [...] Read more.
Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM patients eventually develop resistance to Bz, although the mechanisms of the resistance are poorly understood. Methods: Lysosomal associated membrane protein 2A (LAMP2A) mRNA and protein expression levels were assessed in ex vivo patient samples and a Bz-resistant MM cell line model by in real-rime PCR, western blotting and immunohistochemistry. In vitro modelling of chaperone-mediated autophagy (CMA) activity in response to ER stress were assessed by western blotting and confocal microscopy. The effects of CMA inhibition on MM cell viability and Bz sensitivity in MM cells were assessed by Annexin V/7AAD apoptosis assays using flow cytometry. Results: In this study, there is evidence that CMA, a chaperone-mediated protein degradation pathway, is upregulated in Bz-resistant MM and the inhibition of CMA sensitises resistant cells to Bz. The protein levels of LAMP2A, the rate-limiting factor of the CMA pathway, are significantly increased in MM patients resistant to Bz and within our Bz-resistant cell line model. Bz-resistant cell lines also possessed higher basal CMA activity than the Bz-sensitive parent cell line. In MM cell lines, CMA activity was upregulated in response to ER stress induced by Bz. The inhibition of CMA sensitises Bz-resistant cells to Bz and the combination of CMA inhibition and Bz in vitro had a more cytotoxic effect on myeloma cells than Bz alone. Conclusion: In summary, the upregulation of CMA is a potential mechanism of resistance to Bz and a novel target to overcome Bz-resistant MM. Full article
(This article belongs to the Special Issue Molecular Insights in Multiple Myeloma Pathogenesis)
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15 pages, 2756 KiB  
Article
Comparison of Monoclonal Gammopathies Linked to Poliovirus or Coxsackievirus vs. Other Infectious Pathogens
by Jean Harb, Nicolas Mennesson, Cassandra Lepetit, Maeva Fourny, Margaux Louvois, Adrien Bosseboeuf, Sophie Allain-Maillet, Olivier Decaux, Caroline Moreau, Anne Tallet, Eric Piver, Philippe Moreau, Valéry Salle, Edith Bigot-Corbel and Sylvie Hermouet
Cells 2021, 10(2), 438; https://doi.org/10.3390/cells10020438 - 19 Feb 2021
Cited by 8 | Viewed by 2498
Abstract
Chronic stimulation by infectious pathogens or self-antigen glucosylsphingosine (GlcSph) can lead to monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Novel assays such as the multiplex infectious antigen microarray (MIAA) and GlcSph assays, permit identification of targets for >60% purified monoclonal [...] Read more.
Chronic stimulation by infectious pathogens or self-antigen glucosylsphingosine (GlcSph) can lead to monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Novel assays such as the multiplex infectious antigen microarray (MIAA) and GlcSph assays, permit identification of targets for >60% purified monoclonal immunoglobulins (Igs). Searching for additional targets, we selected 28 purified monoclonal Igs whose antigen was not represented on the MIAA and GlcSph assays; their specificity of recognition was then analyzed using microarrays consisting of 3760 B-cell epitopes from 196 pathogens. The peptide sequences PALTAVETG and PALTAAETG of the VP1 coat proteins of human poliovirus 1/3 and coxsackievirus B1/B3, respectively, were specifically recognized by 6/28 monoclonal Igs. Re-analysis of patient cohorts showed that purified monoclonal Igs from 10/155 MGUS/SM (6.5%) and 3/147 MM (2.0%) bound to the PALTAVETG or PALTAAETG epitopes. Altogether, PALTAV/AETG-initiated MGUS are not rare and few seem to evolve toward myeloma. Full article
(This article belongs to the Special Issue Molecular Insights in Multiple Myeloma Pathogenesis)
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Review

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15 pages, 1566 KiB  
Review
A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics
by Hassan Awada, Bicky Thapa, Hussein Awada, Jing Dong, Carmelo Gurnari, Parameswaran Hari and Binod Dhakal
Cells 2021, 10(8), 1961; https://doi.org/10.3390/cells10081961 - 2 Aug 2021
Cited by 18 | Viewed by 4132
Abstract
Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). [...] Read more.
Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk stratification of MM patients. Full article
(This article belongs to the Special Issue Molecular Insights in Multiple Myeloma Pathogenesis)
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14 pages, 826 KiB  
Review
Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets
by Jessica Burroughs Garcìa, Rosa Alba Eufemiese, Paola Storti, Gabriella Sammarelli, Luisa Craviotto, Giannalisa Todaro, Denise Toscani, Valentina Marchica and Nicola Giuliani
Cells 2021, 10(6), 1360; https://doi.org/10.3390/cells10061360 - 1 Jun 2021
Cited by 22 | Viewed by 4712
Abstract
Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. [...] Read more.
Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon. Full article
(This article belongs to the Special Issue Molecular Insights in Multiple Myeloma Pathogenesis)
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20 pages, 1739 KiB  
Review
Potential Role of microRNAs in inducing Drug Resistance in Patients with Multiple Myeloma
by Alessandro Allegra, Roberta Ettari, Vanessa Innao and Alessandra Bitto
Cells 2021, 10(2), 448; https://doi.org/10.3390/cells10020448 - 20 Feb 2021
Cited by 14 | Viewed by 2929
Abstract
The prognosis for newly diagnosed subjects with multiple myeloma (MM) has significantly progressed in recent years. However, most MM patients relapse and after several salvage therapies, the onset of multidrug resistance provokes the occurrence of a refractory disease. A continuous and bidirectional exchange [...] Read more.
The prognosis for newly diagnosed subjects with multiple myeloma (MM) has significantly progressed in recent years. However, most MM patients relapse and after several salvage therapies, the onset of multidrug resistance provokes the occurrence of a refractory disease. A continuous and bidirectional exchange of information takes place between the cells of the microenvironment and neoplastic cells to solicit the demands of cancer cells. Among the molecules serving as messengers, there are microRNAs (miRNA), a family of small noncoding RNAs that regulate gene expression. Numerous miRNAs are associated with drug resistance, also in MM, and the modulation of their expression or activity might be explored to reverse it. In this review we report the most recent studies concerning the relationship between miRNAs and chemoresistance to the most frequently used drugs, such as proteasome inhibitors, steroids, alkylating agents and immunomodulators. The experimental use of antagomirs or miRNA mimics have successfully been proven to counteract chemoresistance and display synergistic effects with antimyeloma drugs which could represent a fundamental moment to overcome resistance in MM treatment. Full article
(This article belongs to the Special Issue Molecular Insights in Multiple Myeloma Pathogenesis)
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8 pages, 848 KiB  
Brief Report
Risk Alleles for Multiple Myeloma Susceptibility in ADME Genes
by Francesca Scionti, Giuseppe Agapito, Daniele Caracciolo, Caterina Riillo, Katia Grillone, Mario Cannataro, Maria Teresa Di Martino, Pierosandro Tagliaferri, Pierfrancesco Tassone and Mariamena Arbitrio
Cells 2022, 11(2), 189; https://doi.org/10.3390/cells11020189 - 6 Jan 2022
Cited by 5 | Viewed by 1931
Abstract
The cause of multiple myeloma (MM) remains largely unknown. Several pieces of evidence support the involvement of genetic and multiple environmental factors (i.e., chemical agents) in MM onset. The inter-individual variability in the bioactivation, detoxification, and clearance of chemical carcinogens such as asbestos, [...] Read more.
The cause of multiple myeloma (MM) remains largely unknown. Several pieces of evidence support the involvement of genetic and multiple environmental factors (i.e., chemical agents) in MM onset. The inter-individual variability in the bioactivation, detoxification, and clearance of chemical carcinogens such as asbestos, benzene, and pesticides might increase the MM risk. This inter-individual variability can be explained by the presence of polymorphic variants in absorption, distribution, metabolism, and excretion (ADME) genes. Despite the high relevance of this issue, few studies have focused on the inter-individual variability in ADME genes in MM risk. To identify new MM susceptibility loci, we performed an extended candidate gene approach by comparing high-throughput genotyping data of 1936 markers in 231 ADME genes on 64 MM patients and 59 controls from the CEU population. Differences in genotype and allele frequencies were validated using an internal control group of 35 non-cancer samples from the same geographic area as the patient group. We detected an association between MM risk and ADH1B rs1229984 (OR = 3.78; 95% CI, 1.18–12.13; p = 0.0282), PPARD rs6937483 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), SLC28A1 rs8187737 (OR = 11.33; 95% CI, 1.43–89.59; p = 0.005), SLC28A2 rs1060896 (OR = 6.58; 95% CI, 1.42–30.43; p = 0.0072), SLC29A1 rs8187630 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), and ALDH3A2 rs72547554 (OR = 2.46; 95% CI, 0.64–9.40; p = 0.0293). The prognostic value of these genes in MM was investigated in two public datasets showing that shorter overall survival was associated with low expression of ADH1B and SLC28A1. In conclusion, our proof-of-concept findings provide novel insights into the genetic bases of MM susceptibility. Full article
(This article belongs to the Special Issue Molecular Insights in Multiple Myeloma Pathogenesis)
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