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Cancers
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Molecular Features in Multiple Myeloma
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Molecular Features in Multiple Myeloma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 15098

Special Issue Editors

Dr. Domenica Ronchetti

E-Mail Website
Guest Editor
Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
Interests: lymphoid malignancies; molecular pathogenesis of multiple myeloma; coding and non coding RNA transcriptome; lncRNA
Prof. Niccolò Bolli

E-Mail Website
Guest Editor
Universita degli Studi di Milano, Milan, Italy
Interests: multiple myeloma; acute myeloid leukaemia; genomics

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is an incurable type of plasma cell cancer that develops within the bone marrow microenvironment. This malignancy presents a variety of subtypes, presentations, and clinical courses. The definition of specific molecular and prognostic subgroups is affected by the occurrence of great genomic (ploidy alteration, translocations, gene mutations) and transcriptional (coding and non-coding RNA) heterogeneity. A broad spectrum of genetic and epigenetic abnormalities has been linked to the pathogenesis of this cancer, ultimately impacting the growth, survival, and drug sensitivity of MM cells.

In recent years, several high-throughput studies have contributed to deciphering the genetic architecture of this disease; however, thus far, its molecular features have not been exploited in MM treatment, and the myeloma community is still far from defining driver events that might lead to personalized therapy.

The aim of the present Special Issue of Cancers is to present a collection of the latest research regarding possible new molecular alterations underlying MM pathobiology, which might have a functional impact on cell survival within the bone marrow milieu, affect responses to antimyeloma drugs, or promote immune evasion. In addition, manuscripts discussing the current state-of-the-art and future prospects for improving diagnosis, prognosis, and therapies are of interest.

Dr. Domenica Ronchetti
Prof. Niccolò Bolli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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
  • Plasma cell dyscrasia
  • ncRNA
  • Bone marrow microenvironment
  • epigenetics

Published Papers (5 papers)

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Research

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17 pages, 1835 KiB  
Article
Transcriptomic Analysis in Multiple Myeloma and Primary Plasma Cell Leukemia with t(11;14) Reveals Different Expression Patterns with Biological Implications in Venetoclax Sensitivity
by Katia Todoerti, Elisa Taiana, Noemi Puccio, Vanessa Favasuli, Marta Lionetti, Ilaria Silvestris, Massimo Gentile, Pellegrino Musto, Fortunato Morabito, Umberto Gianelli, Niccolò Bolli, Luca Baldini, Antonino Neri and Domenica Ronchetti
Cancers 2021, 13(19), 4898; https://doi.org/10.3390/cancers13194898 - 29 Sep 2021
Cited by 8 | Viewed by 2271
Abstract
Mechanisms underlying the pathophysiology of primary Plasma Cell Leukemia (pPCL) and intramedullary multiple myeloma (MM) need to be further elucidated, being potentially relevant for improving therapeutic approaches. In such a context, the MM and pPCL subgroups characterized by t(11;14) deserve a focused investigation, [...] Read more.
Mechanisms underlying the pathophysiology of primary Plasma Cell Leukemia (pPCL) and intramedullary multiple myeloma (MM) need to be further elucidated, being potentially relevant for improving therapeutic approaches. In such a context, the MM and pPCL subgroups characterized by t(11;14) deserve a focused investigation, as the presence of the translocation is mainly associated with sensitivity to venetoclax. Herein, we investigated a proprietary cohort of MM and pPCL patients, focusing on the transcriptional signature of samples carrying t(11;14), whose incidence increases in pPCL in association with an unfavorable outcome. In addition, we evaluated the expression levels of the BCL2-gene family members and of a panel of B-cell genes recently reported to be associated with sensitivity to venetoclax in MM. Moreover, transcriptional analysis of lncRNAs in the two clinical settings led to the identification of several differentially expressed transcripts, among which the SNGH6 deregulated lncRNA might be relevant in the pathogenesis and prognosis of pPCL with t(11;14). Overall, our data suggest that MMs and pPCLs with t(11;14) might be responsive to venetoclax based on different molecular programs, prompting further studies to elucidate better novel potential predictive biomarkers. Full article
(This article belongs to the Special Issue Molecular Features in Multiple Myeloma)
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Review

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25 pages, 629 KiB  
Review
Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications
by Jacqueline Schütt, Theresa Nägler, Tino Schenk and Annamaria Brioli
Cancers 2021, 13(16), 4069; https://doi.org/10.3390/cancers13164069 - 13 Aug 2021
Cited by 3 | Viewed by 2661
Abstract
Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial [...] Read more.
Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance. Full article
(This article belongs to the Special Issue Molecular Features in Multiple Myeloma)
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13 pages, 837 KiB  
Review
Genomics of Smoldering Multiple Myeloma: Time for Clinical Translation of Findings?
by Marta Lionetti, Matteo C. Da Vià, Francesco Albano, Antonino Neri, Niccolò Bolli and Pellegrino Musto
Cancers 2021, 13(13), 3319; https://doi.org/10.3390/cancers13133319 - 1 Jul 2021
Cited by 3 | Viewed by 3126
Abstract
Smoldering multiple myeloma (SMM) is an asymptomatic disorder of clonal bone marrow (BM) plasma cells (PCs) in between the premalignant condition known as monoclonal gammopathy of undetermined significance and overt multiple myeloma (MM). It is characterized by a deep biological heterogeneity that is [...] Read more.
Smoldering multiple myeloma (SMM) is an asymptomatic disorder of clonal bone marrow (BM) plasma cells (PCs) in between the premalignant condition known as monoclonal gammopathy of undetermined significance and overt multiple myeloma (MM). It is characterized by a deep biological heterogeneity that is reflected in a markedly variable progression risk among patients. Recently proposed risk stratification models mainly rely on indirect markers of disease burden and are unable to identify cases in whom clonal PCs have already undergone the “malignant switch” but major clonal expansion has not occurred yet. In the last years, the application of next-generation sequencing (NGS) techniques has led to profound advances in the understanding of the molecular bases of SMM progression, and in all likelihood, it will contribute to the needed improvement of SMM prognostication. In this Review, we describe the recent advances in characterizing the genomic landscape of SMM and intrinsic determinants of its progression, highlighting their implications in terms of understanding of tumor evolution and prognostication. We also review the main studies investigating the role of the microenvironment in this early disease stage. Finally, we mention the results of the first randomized clinical trials and discuss the potential clinical translability of the genomic insights. Full article
(This article belongs to the Special Issue Molecular Features in Multiple Myeloma)
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13 pages, 1183 KiB  
Review
Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities
by Cirino Botta, Francesco Mendicino, Enrica Antonia Martino, Ernesto Vigna, Domenica Ronchetti, Pierpaolo Correale, Fortunato Morabito, Antonino Neri and Massimo Gentile
Cancers 2021, 13(13), 3213; https://doi.org/10.3390/cancers13133213 - 28 Jun 2021
Cited by 20 | Viewed by 3915
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through [...] Read more.
Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients. Full article
(This article belongs to the Special Issue Molecular Features in Multiple Myeloma)
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21 pages, 1518 KiB  
Review
The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma
by Arantxa Carrasco-León, Ane Amundarain, Nahia Gómez-Echarte, Felipe Prósper and Xabier Agirre
Cancers 2021, 13(8), 1976; https://doi.org/10.3390/cancers13081976 - 20 Apr 2021
Cited by 9 | Viewed by 2323
Abstract
MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer [...] Read more.
MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer regions and extensive DNA hypomethylation of intergenic regions, highlighting the relevance of these non-coding genomic regions. A recent study described how long non-coding RNAs (lncRNAs) correspond to 82% of the MM transcriptome and an increasing number of studies have demonstrated the importance of deregulation of lncRNAs in MM. In this review we focus on the deregulated lncRNAs in MM, including their biological or functional mechanisms, their role as biomarkers to improve the prognosis and monitoring of MM patients, and their participation in drug resistance. Furthermore, we also discuss the evidence supporting the role of lncRNAs as therapeutic targets through different novel RNA-based strategies. Full article
(This article belongs to the Special Issue Molecular Features in Multiple Myeloma)
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