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Molecular and Cellular Biology of Multiple Myeloma
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Molecular and Cellular Biology of Multiple Myeloma

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 11566

Special Issue Editors

Prof. Dr. Antonino Neri

E-Mail Website
Guest Editor
Direzione Scientifica, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
Interests: multiple myeloma; flow cytometry; minimal residual disease; microbiome; next generation sequencing; RNA-seq; immunome; microenvironment; MDSCs
Dr. Alessandra Romano

E-Mail Website
Guest Editor
Dipartimento di Chirurgia e Specialità Medico Chirurgiche, Sezione di Ematologia, Università degli Studi di Catania, Catania, Italy
Interests: hematology
Special Issues, Collections and Topics in MDPI journals
Dr. Matteo Claudio Da Vià

E-Mail Website
Guest Editor
Dipartimento di Oncologia ed Emato-oncologia, Università degli Studi di Milano, 20122 Milano, Italy
Interests: next generation sequencing; hematology leukemia; multiple myeloma; fungal infection; myelodysplastic syndromes; hematopoietic stem cell transplantation; tumor immunology

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells, which can be preceded by asymptomatic and premalignant stages. MM is characterized by a significant biological and clinical heterogeneity and evolves over time, driven by the genotypic and phenotypic features associated with different myeloma cell subpopulations. Furthermore, the crosstalk between MM cells and the bone marrow (BM) microenvironment plays a critical role in MM pathogenesis by promoting (i) tumor cell growth, (ii) cell survival, (iii) drug resistance and (iv) bone disease. Multiple risk factors, such as lipid metabolism, obesity, and age, are associated with the development of MM. Over the last 20 years, developments in disease management, including a combination of various targeting agents and the classical chemotherapeutic regimens, have changed the prognosis and improved the lifespan of patients with MM. However, due to MM’s high heterogeneity and drug resistance, the prognosis of MM is still poor. Despite the progress that has been made in understanding the molecular pathogenesis of MM, many vital questions remain unanswered.

This Research Topic aims to provide a comprehensive overview of the current issues regarding biological and molecular features, their relevance in clinical settings and their effect on the immunotherapeutic strategies that are currently approved or under investigation for Multiple Myeloma. We welcome the submission of Review and Original Research articles that cover, but are not limited to, the following topics: 

  1. Pathogenesis and molecular mechanisms of immune dysfunctions in Multiple Myeloma.
  2. Molecular mechanisms regulating the expression of these molecules on plasma cells and other immune cell types.
  3. Role of checkpoint inhibitors in MM.
  4. Genetic and Epigenetic mechanisms of multiple myeloma
  5. Clonal selection and dynamic evolution of multiple myeloma.

Prof. Dr. Antonino Neri
Dr. Alessandra Romano
Dr. Matteo Claudio Da Vià
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at mdpi.longhoe.net by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multiple myeloma
  • flow cytometry
  • minimal residual disease
  • microbiome
  • next generation sequencing
  • RNA-seq
  • immunome
  • microenvironment
  • MDSCs

Published Papers (5 papers)

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Research

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9 pages, 1655 KiB  
Article
Single-Cell RNA Sequencing for the Detection of Clonotypic V(D)J Rearrangements in Multiple Myeloma
by Antonio Matera, Alessio Marella, Akihiro Maeda, Matteo C. Da Vià, Francesca Lazzaroni, Sonia Fabris, Stefania Pioggia, Laura Porretti, Federico Colombo, Federica Torricelli, Antonino Neri, Elisa Taiana, Giuseppina Fabbiano, Valentina Traini, Elisa Genuardi, Daniela Drandi, Niccolò Bolli and Marta Lionetti
Int. J. Mol. Sci. 2022, 23(24), 15691; https://doi.org/10.3390/ijms232415691 - 10 Dec 2022
Cited by 1 | Viewed by 2176
Abstract
Multiple myeloma (MM) has a highly heterogeneous genetic background, which complicates its molecular tracking over time. Nevertheless, each MM patient’s malignant plasma cells (PCs) share unique V(D)J rearranged sequences at immunoglobulin loci, which represent ideal disease biomarkers. Because the tumor-specific V(D)J sequence is [...] Read more.
Multiple myeloma (MM) has a highly heterogeneous genetic background, which complicates its molecular tracking over time. Nevertheless, each MM patient’s malignant plasma cells (PCs) share unique V(D)J rearranged sequences at immunoglobulin loci, which represent ideal disease biomarkers. Because the tumor-specific V(D)J sequence is highly expressed in bulk RNA in MM patients, we wondered whether it can be identified by single-cell RNA sequencing (scRNA-seq). To this end we analyzed CD138+ cells purified from bone marrow aspirates of 19 samples with PC dyscrasias by both a standard method based on bulk DNA and by an implementation of the standard 10x Genomics protocol to detect expressed V(D)J sequences. A dominant clonotype was easily identified in each sample, accounting on average for 83.65% of V(D)J-rearranged cells. Compared with standard methods, scRNA-seq analysis proved highly concordant and even more effective in identifying clonal productive rearrangements, by-passing limitations related to the misannealing of consensus primers in hypermutated regions. We next validated its accuracy to track 5 clonal cells with absolute sensitivity in a virtual sample containing 3180 polyclonal cells. This shows that single-cell V(D)J analysis may be used to find rare clonal cells, laying the foundations for functional single-cell dissection of minimal residual disease. Full article
(This article belongs to the Special Issue Molecular and Cellular Biology of Multiple Myeloma)
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12 pages, 1688 KiB  
Article
Identification of a Maturation Plasma Cell Index through a Highly Sensitive Droplet Digital PCR Assay Gene Expression Signature Validation in Newly Diagnosed Multiple Myeloma Patients
by Marina Martello, Vincenza Solli, Rosalinda Termini, Ajsi Kanapari, Daniel Remondini, Enrica Borsi, Andrea Poletti, Silvia Armuzzi, Barbara Taurisano, Ilaria Vigliotta, Gaia Mazzocchetti, Elena Zamagni, Alessandra Merlotti, Paola Tacchetti, Lucia Pantani, Serena Rocchi, Ilaria Rizzello, Katia Mancuso, Michele Cavo and Carolina Terragna
Int. J. Mol. Sci. 2022, 23(20), 12450; https://doi.org/10.3390/ijms232012450 - 18 Oct 2022
Cited by 1 | Viewed by 3031
Abstract
DNA microarrays and RNA-based sequencing approaches are considered important discovery tools in clinical medicine. However, cross-platform reproducibility studies undertaken so far have highlighted that microarrays are not able to accurately measure gene expression, particularly when they are expressed at low levels. Here, we [...] Read more.
DNA microarrays and RNA-based sequencing approaches are considered important discovery tools in clinical medicine. However, cross-platform reproducibility studies undertaken so far have highlighted that microarrays are not able to accurately measure gene expression, particularly when they are expressed at low levels. Here, we consider the employment of a digital PCR assay (ddPCR) to validate a gene signature previously identified by gene expression profile. This signature included ten Hedgehog (HH) pathways’ genes able to stratify multiple myeloma (MM) patients according to their self-renewal status. Results show that the designed assay is able to validate gene expression data, both in a retrospective as well as in a prospective cohort. In addition, the plasma cells’ differentiation status determined by ddPCR was further confirmed by other techniques, such as flow cytometry, allowing the identification of patients with immature plasma cells’ phenotype (i.e., expressing CD19+/CD81+ markers) upregulating HH genes, as compared to others, whose plasma cells lose the expression of these markers and were more differentiated. To our knowledge, this is the first technical report of gene expression data validation by ddPCR instead of classical qPCR. This approach permitted the identification of a Maturation Index through the integration of molecular and phenotypic data, able to possibly define upfront the differentiation status of MM patients that would be clinically relevant in the future. Full article
(This article belongs to the Special Issue Molecular and Cellular Biology of Multiple Myeloma)
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20 pages, 3570 KiB  
Article
Prognostic Value of Association of Copy Number Alterations and Cell-Surface Expression Markers in Newly Diagnosed Multiple Myeloma Patients
by Mihaiela L. Dragoș, Iuliu C. Ivanov, Mihaela Mențel, Irina C. Văcărean-Trandafir, Adriana Sireteanu, Amalia A. Titianu, Angela S. Dăscălescu, Alexandru B. Stache, Daniela Jitaru and Dragoș L. Gorgan
Int. J. Mol. Sci. 2022, 23(14), 7530; https://doi.org/10.3390/ijms23147530 - 7 Jul 2022
Cited by 2 | Viewed by 1691
Abstract
Multiple myeloma results from the clonal proliferation of abnormal plasma cells (PCs) in the bone marrow (BM). In this study, the cell surface expression markers (CD) on atypical PCs (detected by multiparametric flow cytometry (MFC)) were correlated with copy number alterations (CNAs) in [...] Read more.
Multiple myeloma results from the clonal proliferation of abnormal plasma cells (PCs) in the bone marrow (BM). In this study, the cell surface expression markers (CD) on atypical PCs (detected by multiparametric flow cytometry (MFC)) were correlated with copy number alterations (CNAs) in the genome (detected by multiplex ligation-dependent probe amplification (MLPA)) to assess their impact on prognosis in newly diagnosed MM patients. Statistically significant results were obtained when different stages of PC maturation (classified based on CD19 and CD81 expression) were associated with CD117 expression and identified CNAs. In the intermediately differentiated PC group (CD19(−) CD81(+)), patients who didn’t express CD117 had a lower median progression free survival (PFS) (p = 0.024). Moreover, within this group, patients with less than three adverse CNAs, which harbor CD117, had a better outcome with a PFS of more than 48 months compared with 19 months (p = 0.008). Considering all the results, our study suggested the need to integrate both the CD markers and copy number alterations to evaluate the prognosis of newly diagnosed multiple myeloma patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Biology of Multiple Myeloma)
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Review

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30 pages, 2784 KiB  
Review
Normalization of the Immunological Microenvironment and Sustained Minimal Residual Disease Negativity: Do We Need Both for Long-Term Control of Multiple Myeloma?
by Giuseppe Bertuglia, Lorenzo Cani, Alessandra Larocca, Francesca Gay and Mattia D’Agostino
Int. J. Mol. Sci. 2022, 23(24), 15879; https://doi.org/10.3390/ijms232415879 - 14 Dec 2022
Cited by 2 | Viewed by 1969
Abstract
Over the past two decades, the treatment landscape for multiple myeloma (MM) has progressed significantly, with the introduction of several new drug classes that have greatly improved patient outcomes. At present, it is well known how the bone marrow (BM) microenvironment (ME) exerts [...] Read more.
Over the past two decades, the treatment landscape for multiple myeloma (MM) has progressed significantly, with the introduction of several new drug classes that have greatly improved patient outcomes. At present, it is well known how the bone marrow (BM) microenvironment (ME) exerts an immunosuppressive action leading to an exhaustion of the immune system cells and promoting the proliferation and sustenance of tumor plasma cells. Therefore, having drugs that can reconstitute a healthy BM ME can improve results in MM patients. Recent findings clearly demonstrated that achieving minimal residual disease (MRD) negativity and sustaining MRD negativity over time play a pivotal prognostic role. However, despite the achievement of MRD negativity, patients may still relapse. The understanding of immunologic changes in the BM ME during treatment, complemented by a deeper knowledge of plasma cell genomics and biology, will be critical to develop future therapies to sustain MRD negativity over time and possibly achieve an operational cure. In this review, we focus on the components of the BM ME and their role in MM, on the prognostic significance of MRD negativity and, finally, on the relative contribution of tumor plasma cell biology and BM ME to long-term disease control. Full article
(This article belongs to the Special Issue Molecular and Cellular Biology of Multiple Myeloma)
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18 pages, 1276 KiB  
Review
Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma
by Nicolas Thomas Iannozzi, Valentina Marchica, Denise Toscani, Jessica Burroughs Garcìa, Nicola Giuliani and Paola Storti
Int. J. Mol. Sci. 2022, 23(24), 15448; https://doi.org/10.3390/ijms232415448 - 7 Dec 2022
Cited by 2 | Viewed by 2139
Abstract
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays [...] Read more.
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM. Full article
(This article belongs to the Special Issue Molecular and Cellular Biology of Multiple Myeloma)
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