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Signaling Pathways in Multiple Myeloma

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

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 33804

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Special Issue Editors

Dr. Paola Storti

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Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
Interests: multiple myeloma; plasma cell biology; plasma cell–microenvironment interactions; angiogenesis; plasma cell transcriptome; smoldering myeloma; monoclonal gammopathy of uncertain significance; hypoxia; monoclonal antibodies

Prof. Dr. Nicola Giuliani

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Guest Editor

Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
Interests: multiple myeloma; hematologic cancers; plasma cell biology; bone lesions; bone microenvironment; angiogenesis; smoldering myeloma; monoclonal gammopathy of uncertain significance; hypoxia; monoclonal antibodies; immunomodulatory drugs; proteasome inhibitors
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Prof. Dr. Klaus Podar

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Department of Internal Medicine II, University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
Interests: multiple myeloma; breast cancer; signal transduction; tumor microenvironment; angiogenesis; bone disease; targeted therapy; apoptosis
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Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is a plasma cell dyscrasia determined by an accumulation of malignant plasma cells in the bone marrow (BM). MM cell proliferation is deregulated by primary or secondary genetic alterations that alter proliferative pathways or cell cycle regulators and by metabolic modifications.

Moreover, the major characteristic of MM is that plasma cells are dependent on the bone marrow cells. In particular, the BM hypoxic microenvironment supports the growth of the malignant clone by upregulation of transcription factors and production of soluble molecules that increase BM angiogenesis and bone destruction. Furthermore, the MM cells have a tight crosstalk with bone cells, such as mesenchymal cells, osteoblasts (OBs), and osteoclasts (OCs) that produce MM proliferation factors and increase resistance to drugs. On the other hand, the balance between OB and OC functions is deregulated by MM cells, leading to the formation of bone lesions.

Finally, the immune microenvironment in MM is also altered with an expansion of regulatory and immunosuppressive cell populations and the production of immunosuppressive molecules by MM cells and BM microenvironment cells.

This Special Issue of Cancers aims to present a collection of original research articles and reviews on pathways implicated in MM biology and pathophysiology.

Dr. Paola Storti
Prof. Dr. Nicola Giuliani
Prof. Klaus Podar
Guest Editors

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Keywords

multiple myeloma
pathways
proliferation
hypoxia
bone lesions
angiogenesis
immunosuppression

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Published Papers (9 papers)

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Research

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18 pages, 2523 KiB

Open AccessArticle

Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma

by Basudev Chowdhury, Swati Garg, Wei Ni, Martin Sattler, Dana Sanchez, Chengcheng Meng, Taisei Akatsu, Richard Stone, William Forrester, Edmund Harrington, Sara J. Buhrlage, James D. Griffin and Ellen Weisberg

Cancers 2024, 16(7), 1319; https://doi.org/10.3390/cancers16071319 - 28 Mar 2024

Cited by 2 | Viewed by 2057

Abstract

Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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22 pages, 2837 KiB

Open AccessArticle

CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma

by Anna Fregnani, Lara Saggin, Ketty Gianesin, Laura Quotti Tubi, Marco Carraro, Gregorio Barilà, Greta Scapinello, Giorgia Bonetto, Maria Pesavento, Tamara Berno, Antonio Branca, Carmela Gurrieri, Renato Zambello, Gianpietro Semenzato, Livio Trentin, Sabrina Manni and Francesco Piazza

Cancers 2022, 14(17), 4173; https://doi.org/10.3390/cancers14174173 - 29 Aug 2022

Cited by 5 | Viewed by 2057

Abstract

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling. CK1α is a negative regulator of the Wnt/β-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM–MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/β-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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15 pages, 3819 KiB

Open AccessArticle

Role of Serum Free Light Chain Assay in Relapsed/Refractory Multiple Myeloma. A Real-Life Unicentric Retrospective Study

by Uros Markovic, Alessandra Romano, Claudia Bellofiore, Annalisa Condorelli, Bruno Garibaldi, Anna Bulla, Andrea Duminuco, Vittorio Del Fabro, Francesco Di Raimondo and Concetta Conticello

Cancers 2021, 13(23), 6017; https://doi.org/10.3390/cancers13236017 - 29 Nov 2021

Cited by 3 | Viewed by 2268

Abstract

Background: In the era of novel drugs a growing number of multiple myeloma (MM) patients are treated until disease progression. Serum free light chain (sFLC) assay is recommended for disease monitoring in oligo-secretory and micromolecular MM. Methods: In this real-life survey, a total of 130 relapsed/refractory MM patients treated at our center with at least three lines were investigated as a retrospective cohort. Results: The median age at diagnosis was 64 years and more than half of patients were male. A total of 24 patients (18%) had oligo-secretory/micromolecular disease at diagnosis. More than 20% of 106 normo-secretory patients had oligo-secretory/micromolecular escape. In order to evaluate potential role of sFLC assay before (“pre”) and after (“post”) every treatment line, involved serum free light chain values (iFLC) less than 138 mg/mL and serum free light chain ratios (FLCr) <25 were identified by using ROC curve analysis. The analysis of the entire cohort throughout four treatment lines demonstrated a statistically significant negative impact on progression-free survival (PFS) for both involved pre-sFLC and its ratio (respectively p = 0.0086 and p = 0.0065). Furthermore, both post-iFLC and post-FLCr greater than the pre-established values had a negative impact on PFS of the study cohort; respectively, p = 0.014 and p = 0.0079. Odds ratio analysis evidenced that patients with both involved post-sFLC greater than 138 mg/mL and post-FLCr above 25 at disease relapse had a higher probability of having clinical relapse (respectively p = 0.026 and p = 0.006). Conclusions: Alterations of sFLC values, namely iFLC and FLCr, both prior to treatment initiation and in the course of therapy at every treatment line, could be of aid in relapse evaluation and treatment outcome. We therefore suggest close periodical monitoring of sFLC assay, independently from secretory status. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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14 pages, 4512 KiB

Open AccessArticle

Dissecting the Biological Relevance and Clinical Impact of lncRNA MIAT in Multiple Myeloma

by Katia Todoerti, Domenica Ronchetti, Noemi Puccio, Ilaria Silvestris, Vanessa Favasuli, Nicola Amodio, Massimo Gentile, Fortunato Morabito, Antonino Neri and Elisa Taiana

Cancers 2021, 13(21), 5518; https://doi.org/10.3390/cancers13215518 - 3 Nov 2021

Cited by 1 | Viewed by 1949

Abstract

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an essential aspect of the investigation, which may contribute to understanding the disease’s complex pathobiology, providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the clinical relevance of the lncRNA MIAT in MM, taking advantage of the publicly available CoMMpass database. MIAT expression in MM is highly heterogeneous and significantly associated with specific molecular lesions frequently occurring in MM. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of MIAT in different signaling pathways and ribosome biogenesis and assembly. These findings suggest that MIAT deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and, indirectly, the translational process. Although MIAT expression levels seem not to be significantly associated with clinical outcome in multivariate analyses, high MIAT expression levels are associated with bortezomib resistance, this suggesting that MIAT targeting could overcome drug resistance in MM. These findings strongly prompt for further studies investigating the significance of MIAT in MM. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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15 pages, 1457 KiB

Open AccessArticle

Multiple Myeloma Relapse Is Associated with Increased NFκB Pathway Activity and Upregulation of the Pro-Survival BCL-2 Protein BFL-1

by Ingrid Spaan, Anja van de Stolpe, Reinier A. Raymakers and Victor Peperzak

Cancers 2021, 13(18), 4668; https://doi.org/10.3390/cancers13184668 - 17 Sep 2021

Cited by 7 | Viewed by 3001

Abstract

Multiple myeloma (MM) is a hematological malignancy that is still considered incurable due to the development of therapy resistance and subsequent relapse of disease. MM plasma cells (PC) use NFκB signaling to stimulate cell growth and disease progression, and for protection against therapy-induced apoptosis. Amongst its diverse array of target genes, NFκB regulates the expression of pro-survival BCL-2 proteins BCL-XL, BFL-1, and BCL-2. A possible role for BFL-1 in MM is controversial, since BFL-1, encoded by BCL2A1, is downregulated when mature B cells differentiate into antibody-secreting PC. NFκB signaling can be activated by many factors in the bone marrow microenvironment and/or induced by genetic lesions in MM PC. We used the novel signal transduction pathway activity (STA) computational model to quantify the functional NFκB pathway output in primary MM PC from diverse patient subsets at multiple stages of disease. We found that NFκB pathway activity is not altered during disease development, is irrespective of patient prognosis, and does not predict therapy outcome. However, disease relapse after treatment resulted in increased NFκB pathway activity in surviving MM PC, which correlated with increased BCL2A1 expression in a subset of patients. This suggests that BFL-1 upregulation, in addition to BCL-XL and BCL-2, may render MM PC resistant to therapy-induced apoptosis, and that BFL-1 targeting could provide a new approach to reduce therapy resistance in a subset of relapsed/refractory MM patients. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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Review

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15 pages, 629 KiB

Open AccessReview

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

by Oronza A. Botrugno and Giovanni Tonon

Cancers 2022, 14(1), 25; https://doi.org/10.3390/cancers14010025 - 22 Dec 2021

Cited by 6 | Viewed by 3436

Abstract

Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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23 pages, 1706 KiB

Open AccessReview

Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma

by Shih-Feng Cho, Lijie Xing, Kenneth C. Anderson and Yu-Tzu Tai

Cancers 2021, 13(23), 6136; https://doi.org/10.3390/cancers13236136 - 6 Dec 2021

Cited by 24 | Viewed by 5808

Abstract

The incorporation of novel agents in recent treatments in multiple myeloma (MM) has improved the clinical outcome of patients. Specifically, the approval of monoclonal antibody (MoAb) against CD38 (daratumumab) and SLAMF7 (elotuzumab) in relapsed and refractory MM (RRMM) represents an important milestone in the development of targeted immunotherapy in MM. These MoAb-based agents significantly induce cytotoxicity of MM cells via multiple effector-dependent mechanisms and can further induce immunomodulation to repair a dysfunctional tumor immune microenvironment. Recently, targeting B cell maturation antigen (BCMA), an even MM-specific antigen, has shown high therapeutic activities by chimeric antigen receptor T cells (CAR T), antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE), as well as bispecific antibody (BiAb), with some already approved for heavily pretreated RRMM patients. New antigens, such as orphan G protein-coupled receptor class C group 5 member D (GPRC5D) and FcRH5, were identified and rapidly moved to ongoing clinical studies. We here summarized the pathobiological function of key MM antigens and the status of the corresponding immunotherapies. The potential challenges and emerging treatment strategies are also discussed. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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16 pages, 2277 KiB

Open AccessReview

The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

by Fengjuan Fan and Klaus Podar

Cancers 2021, 13(10), 2326; https://doi.org/10.3390/cancers13102326 - 12 May 2021

Cited by 25 | Viewed by 7198

Abstract

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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32 pages, 16373 KiB

Open AccessReview

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

by Tina Paradzik, Cecilia Bandini, Elisabetta Mereu, Maria Labrador, Elisa Taiana, Nicola Amodio, Antonino Neri and Roberto Piva

Cancers 2021, 13(6), 1235; https://doi.org/10.3390/cancers13061235 - 11 Mar 2021

Cited by 17 | Viewed by 4718

Abstract

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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