International Journal of Molecular Sciences

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Open AccessEditorial

Editorial: Multiple Myeloma: Molecular Mechanism and Targeted Therapy

by Despina Bazou and Paul Dowling

Int. J. Mol. Sci. 2024, 25(7), 3799; https://doi.org/10.3390/ijms25073799 - 28 Mar 2024

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Abstract

Multiple myeloma (MM) is a plasma cell disorder representing the second most common blood cancer [...] Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

Research

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16 pages, 3373 KiB

Open AccessArticle

Upregulated Expression of ERBB2/HER2 in Multiple Myeloma as a Predictor of Poor Survival Outcomes

by Fatih M. Uckun and Sanjive Qazi

Int. J. Mol. Sci. 2023, 24(12), 9943; https://doi.org/10.3390/ijms24129943 - 9 Jun 2023

Cited by 2 | Viewed by 1233

Abstract

The main goal of the present study was to examine if the RNA-sequencing (RNAseq)-based ERBB2/HER2 expression level in malignant plasma cells from multiple myeloma (MM) patients has clinical significance for treatment outcomes and survival. We examined the relationship between the RNAseq-based ERBB2 messenger [...] Read more.

The main goal of the present study was to examine if the RNA-sequencing (RNAseq)-based ERBB2/HER2 expression level in malignant plasma cells from multiple myeloma (MM) patients has clinical significance for treatment outcomes and survival. We examined the relationship between the RNAseq-based ERBB2 messenger ribonucleic acid (mRNA) levels in malignant plasma cells and survival outcomes in 787 MM patients treated on contemporary standard regimens. ERBB2 was expressed at significantly higher levels than ERBB1 as well as ERBB3 across all three stages of the disease. Upregulated expression of ERBB2 mRNA in MM cells was correlated with amplified expression of mRNAs for transcription factors (TF) that recognize the ERBB2 gene promoter sites. Patients with higher levels of ERBB2 mRNA in their malignant plasma cells experienced significantly increased cancer mortality, shorter progression-free survival, and worse overall survival than other patients. The adverse impact of high ERBB2 expression on patient survival outcomes remained significant in multivariate Cox proportional hazards models that accounted for the effects of other prognostic factors. To the best of our knowledge, this is the first demonstration of an adverse prognostic impact of high-level ERBB2 expression in MM patients. Our results encourage further evaluation of the prognostic significance of high-level ERBB2 mRNA expression and the clinical potential of ERBB2-targeting therapeutics as personalized medicines to overcome cancer drug resistance in high-risk as well as relapsed/refractory MM. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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20 pages, 3502 KiB

Open AccessArticle

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

by Esther Clavero, José Manuel Sanchez-Maldonado, Angelica Macauda, Rob Ter Horst, Belém Sampaio-Marques, Artur Jurczyszyn, Alyssa Clay-Gilmour, Angelika Stein, Michelle A. T. Hildebrandt, Niels Weinhold, Gabriele Buda, Ramón García-Sanz, Waldemar Tomczak, Ulla Vogel, Andrés Jerez, Daria Zawirska, Marzena Wątek, Jonathan N. Hofmann, Stefano Landi, John J. Spinelli, Aleksandra Butrym, Abhishek Kumar, Joaquín Martínez-López, Sara Galimberti, María Eugenia Sarasquete, Edyta Subocz, Elzbieta Iskierka-Jażdżewska, Graham G. Giles, Malwina Rybicka-Ramos, Marcin Kruszewski, Niels Abildgaard, Francisco García Verdejo, Pedro Sánchez Rovira, Miguel Inacio da Silva Filho, Katalin Kadar, Małgorzata Razny, Wendy Cozen, Matteo Pelosini, Manuel Jurado, Parveen Bhatti, Marek Dudzinski, Agnieszka Druzd-Sitek, Enrico Orciuolo, Yang Li, Aaron D. Norman, Jan Maciej Zaucha, Rui Manuel Reis, Miroslaw Markiewicz, Juan José Rodríguez Sevilla, Vibeke Andersen, Krzysztof Jamroziak, Kari Hemminki, Sonja I. Berndt, Vicent Rajkumar, Grzegorz Mazur, Shaji K. Kumar, Paula Ludovico, Arnon Nagler, Stephen J. Chanock, Charles Dumontet, Mitchell J. Machiela, Judit Varkonyi, Nicola J. Camp, Elad Ziv, Annette Juul Vangsted, Elizabeth E. Brown, Daniele Campa, Celine M. Vachon, Mihai G. Netea, Federico Canzian, Asta Försti and Juan Sainz Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(10), 8500; https://doi.org/10.3390/ijms24108500 - 9 May 2023

Cited by 4 | Viewed by 3432

Abstract

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, [...] Read more.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10⁻⁹) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10⁻⁴−5.79 × 10⁻¹⁴). Mechanistically, we found that the ULK4_rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10⁻⁴), whereas the IKBKE_rs17433804 SNP correlated with the number of transitional CD24⁺CD38⁺ B cells (p = 4.8 × 10⁻⁴) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10⁻⁴). We also found that the CD46_rs1142469 SNP correlated with numbers of CD19⁺ B cells, CD19⁺CD3⁻ B cells, CD5⁺IgD⁻ cells, IgM⁻ cells, IgD⁻IgM⁻ cells, and CD4⁻CD8⁻ PBMCs (p = 4.9 × 10⁻⁴−8.6 × 10⁻⁴) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2A_rs2811710 SNP correlated with levels of CD4⁺EMCD45RO⁺CD27⁻ cells (p = 9.3 × 10⁻⁴). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3⁻, MCP-2⁻, and IL20-dependent pathways. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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20 pages, 3343 KiB

Open AccessArticle

Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib

by P. M. Rojas-Zambrano, J. E. Meyer-Herrera, P. F. Ruiz-Aparicio and J. P. Vernot

Int. J. Mol. Sci. 2023, 24(9), 8157; https://doi.org/10.3390/ijms24098157 - 2 May 2023

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Abstract

Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has [...] Read more.

Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-κB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-κB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma. Considering that H929 cells were also directly susceptible to PKC and NF-κB inhibition, we showed that treatment of co-cultures with the HKPS peptide and BAY11-7082, followed by bortezomib, increased H929 cell death. Therefore, targeting simultaneously connected signalling elements of BM-MSC responsible for MM cells support with compounds that also have anti-MM activity can be an improved treatment strategy. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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12 pages, 747 KiB

Open AccessArticle

The Relationship between Serum miRNAs and Early Mortality in Multiple Myeloma Patients Treated with Bortezomib-Based Regimens

by Anna Puła, Paweł Robak, Dariusz Jarych, Damian Mikulski, Małgorzata Misiewicz, Izabela Drozdz, Wojciech Fendler, Janusz Szemraj and Tadeusz Robak

Int. J. Mol. Sci. 2023, 24(3), 2938; https://doi.org/10.3390/ijms24032938 - 2 Feb 2023

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Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment. Despite the progress made in treatment, some MM patients still die within the first year of diagnosis. Numerous studies investigating microRNA (miRNA) [...] Read more.

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment. Despite the progress made in treatment, some MM patients still die within the first year of diagnosis. Numerous studies investigating microRNA (miRNA) expression patterns suggest they may be good prognostic markers. The primary aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients who were later treated with bortezomib-based regimens, and to determine their potential to predict early mortality. The study was conducted in 70 prospectively recruited patients with newly diagnosed MM admitted to the Department of Hematology of the Copernicus Memorial Hospital, Lodz (Poland) between 2017 and 2021. Among them, 17 patients experienced death within 12 months of diagnosis. The expression of 31 selected miRNAs was determined using a miRCURY LNA miRNA Custom PCR Panel. The obtained clinical data included patient characteristics on diagnosis, treatment regimen, response to treatment, and follow-up. Differential expression analysis found two miRNAs to be significantly downregulated in the early mortality group: hsa-miR-328-3p (fold change—FC: 0.72, p = 0.0342) and hsa-miR-409-3p (FC: 0.49, p = 0.0357). Univariate and multivariate logistic regression analyses were performed to assess the early mortality rate. The final model consisted of hsa-miR-409-3p, hsa-miR-328-3p, age, and R-ISS 3. It yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761–0.965) with 88.2% sensitivity and 77.5% specificity. Further external validation of our model is needed to confirm its clinical value. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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Review

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11 pages, 603 KiB

Open AccessReview

Bleeding and Thrombosis in Multiple Myeloma: Platelets as Key Players during Cell Interactions and Potential Use as Drug Delivery Systems

by Anushka Kulkarni, Despina Bazou and Maria José Santos-Martinez

Int. J. Mol. Sci. 2023, 24(21), 15855; https://doi.org/10.3390/ijms242115855 - 1 Nov 2023

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Abstract

Multiple myeloma (MM) is a hematological malignancy originated in the bone marrow and characterized by unhindered plasma cell proliferation that results in several clinical manifestations. Although the main role of blood platelets lies in hemostasis and thrombosis, platelets also play a pivotal role [...] Read more.

Multiple myeloma (MM) is a hematological malignancy originated in the bone marrow and characterized by unhindered plasma cell proliferation that results in several clinical manifestations. Although the main role of blood platelets lies in hemostasis and thrombosis, platelets also play a pivotal role in a number of other pathological conditions. Platelets are the less-explored components from the tumor microenvironment in MM. Although some studies have recently revealed that MM cells have the ability to activate platelets even in the premalignant stage, this phenomenon has not been widely investigated in MM. Moreover, thrombocytopenia, along with bleeding, is commonly observed in those patients. In this review, we discuss the hemostatic disturbances observed in MM patients and the dynamic interaction between platelets and myeloma cells, along with present and future potential avenues for the use of platelets for diagnostic and therapeutic purposes. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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12 pages, 560 KiB

Open AccessReview

Genetic Abnormalities in Extramedullary Multiple Myeloma

by Roisin McAvera, John Quinn, Philip Murphy and Siobhan Glavey

Int. J. Mol. Sci. 2023, 24(14), 11259; https://doi.org/10.3390/ijms241411259 - 9 Jul 2023

Cited by 3 | Viewed by 1584

Abstract

Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an [...] Read more.

Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an extremely poor prognosis. In the era of novel agents and anti-myeloma therapies, the incidence of EMD is increasing, making this a more prevalent and challenging cohort of patients. Therefore, understanding the underlying mechanisms of bone marrow escape and EMD driver events is increasingly urgent. The role of genomics in MM has been studied extensively; however, much less is known about the genetic background of EMD. Recently there has been an increased focus on driver events for the establishment of distant EMD sites. Generally, high-risk cytogenetic abnormalities and gene signatures are associated with EMD, alongside mutations in RAS signalling pathways. More recently, changes in epigenetic regulation have also been documented, specifically the hypermethylation of DNA promoter regions. Therefore, the focus of this review is to summarize and discuss what is currently known about the genetic background of EMD in MM. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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Other

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12 pages, 1869 KiB

Open AccessHypothesis

Macrophages and Urokinase Plasminogen Activator Receptor System in Multiple Myeloma: Case Series and Literature Review

by Paola Manzo, Valentina Giudice, Filomena Napolitano, Danilo De Novellis, Bianca Serio, Paolo Moscato, Nunzia Montuori and Carmine Selleri

Int. J. Mol. Sci. 2023, 24(13), 10519; https://doi.org/10.3390/ijms241310519 - 23 Jun 2023

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Abstract

The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes [...] Read more.

The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; p = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; p = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies. Full article

(This article belongs to the Special Issue Multiple Myeloma: Molecular Mechanism and Targeted Therapy)

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