- 1Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy
- 2Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
- 3National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
Editorial on the Research Topic
Molecular Mechanisms of Multiple Myeloma
Multiple myeloma (MM) is a plasma cell disorder representing the second most common blood cancer (1). MM is still defined as an incurable disease, but survival has nearly doubled in latest years due to novel drugs and novel therapeutic strategies (Gozzetti et al., 2–4). Also, high-risk MM had benefited from novel therapies, although with less potency (5–8). Knowledge of the molecular mechanisms and pathogenesis of MM is behind this progress, in particular genetics of the monoclonal plasma cells and their interactions with the microenvironment (9, 10).
MM cell proliferation and apoptosis are touched by the paper entitled “Study of Tim3 regulation in multiple myeloma cell proliferation via NF-kB signal pathways” (Liu et al.). T-cell immunoglobulin and mucin domain-3 (Tim3) is a negative regulatory factor of cellular immunity (11). In this study, Liu et al. found a higher expression of Tim3 by flow cytometry in bone marrow plasma cells derived from 167 MM patients when compared with 51 healthy donors. Additionally, higher Tim3 expression level was associated with poorer prognostic factor based on International Staging System (ISS) stage III when compared to stage I and II. Mechanistically, the authors showed that cell proliferation was decreased, and apoptosis was induced via NF-kB signaling upon Tim3 knocked-down in vitro by siRNA using two MM cell lines. Furthermore, the authors observed that Tim3 knockdown used in combination with the anti-myeloma therapy bortezomib had an additive effect on apoptosis in MM cell lines. This suggests that Tim3 may be a potential therapeutic target.
Host immunity is crucial in antitumor activity. In the paper entitled “Metabolic reprogramming induces immune cell dysfunction in the tumor microenvironment of multiple myeloma”, Wu et al. review data about metabolic reprogramming in MM, which is associated with the hypoxic, acidic, and nutritionally deficient microenvironment. In particular, authors remark how these findings can negatively impact the anti-tumor activity of the immune cells, i.e. T-cell mediated tumor lysis via silencing of PTPN1, TP53I11 induced by hypoxia (12, Wegiel et al.), reduced NK activity by decreased ligand receptors RAE-1 and PVR on MM cells (13) and PD-L1 upregulation via HIF-1a (14).
Metabolic abnormalities are important in cancer, age, obesity can be cancer-promoting factors and can affect also disease responsiveness and progression. Lazaris et al. in the paper “The lipoprotein transport system in the pathogenesis of multiple myeloma: advances and challenges,” review the role of bone marrow adipocytes to support growth and proliferation of MM plasma cells and bone remodeling (15, 16). The deregulation of the lipoprotein system seems to correlate with MM development together with obesity. Interestingly, different studies looked at serum lipid assessment in MM patients during treatment and one found higher APOA1 (the major apolipoprotein of high-density lipoprotein HDL) related to better survival (17–19).
Methylation has been reported to be present in MM (20), although hypomethylating agents are not very much used in clinical practice. The paper “KDM2A targets PFKB3 for ubiquitylation to inhibit the proliferation and angiogenesis of multiple myeloma cells” by Liu et al. showed that the lysine demethylase KDM2A acts not only as an epigenetic regulator in cancer but also as an inhibitor of MM plasma cells proliferation and angiogenesis through ubiquitination of PFKB3, a crucial enzyme in glycolysis (21, 22). Moreover, IL-32 and the vascular endothelial growth factor (VEGF), direct key players in promoting angiogenesis, were measured and found increased in knockdown KDM2A MM cells. These findings suggest KDM2A ubiquitination of PFKB3 as a possible therapeutic target in myeloma.
Extramedullary MM (EMM) represents an unmet clinical need in daily practice (23–25). Even though new drugs increased the percentage of responses in this field, the prognosis is still poor. Much remains unknown on the molecular basis of EMM. In the last article, “Intratumor heterogeneity of MIF expression correlates with extramedullary involvement in myeloma,” Xu et al. highlight the role of MIF (macrophage migration inhibitory factor) expression in the development of EMM. In particular, authors found low levels of MIF expression in extramedullary biopsies of 17 patients compared to intramedullary biopsies. MIF high expression induced high proliferation of MM cells in in vivo mouse models, suggesting a role for MIF in EMM.
Altogether these studies highlight the different molecular mechanisms of MM development and aggressiveness and suggest a possible new target for MM therapy.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Acknowledgments
The Topic Editors thank all the contributors for submitting their work to this Research Topic, to the Review Editors and external Reviewers who participated in the review process, and to the Editorial and Production teams of Frontiers for their support through the various stages of the publication process.
References
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin (2021) 71(1):7–33. doi: 10.3322/caac.21654
2. Mohty M, Terpos E, Mateos MV, Cavo M, Lejniece S, Beksac M, et al. EMMOS Investigators. Multiple Myeloma Treatment in Real-World Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study. Clin Lymphoma Myeloma Leuk (2018) 18:e401–19. doi: 10.1016/j.clml.2018.06.018
3. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved Survival in Multiple Myeloma and the Impact of Novel Therapies. Blood (2008) 111:2516–20. doi: 10.1182/blood-2007-10-116129
4. Ocio EM, Richardson PG, Rajkumar SV, Palumbo A, Mateos MV, Orlowski R, et al. New Drugs and Novel Mechanisms of Action in Multiple Myeloma 2013: A Report From the International Myeloma Working Group (IMWG). Leukemia (2014) 28:525–42. doi: 10.1038/leu.2013.350
5. Gozzetti A, Cerase A, Lotti F, Rossi D, Palumbo A, Petrucci MT, et al. Extramedullary Intracranial Localization of Multiple Myeloma and Treatment With Novel Agents: A Retrospective Survey of 50 Patients. Cancer (2012) 118:1574–84. doi: 10.1002/cncr.26447
6. Gozzetti A, Cerase A. Novel Agents in CNS Myeloma Treatment. Cent Nerv Syst Agents Med Chem (2014) 14:23–7. doi: 10.2174/1871524914999140818111514
7. Castillo JJ, Jurczyszyn A, Brozova L, Crusoe E, Czepiel J, Davila J, et al. IgM Myeloma: A Multicenter Retrospective Study of 134 Patients. Am J Hematol (2017) 92(8):746–51. doi: 10.1002/ajh.24753
8. Jurczyszyn A, Radocha J, Davila J, Fiala MA, Gozzetti A, Grząśko N, et al. Prognostic Indicators in Primary Plasma Cell Leukaemia: A Multicentre Retrospective Study of 117 Patients. Br J Haematol (2018) 180(6):831–39. doi: 10.1111/bjh.15092
9. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding Multiple Myeloma Pathogenesis in the Bone Marrow to Identify New Therapeutic Targets. Nat Rev Cancer (2007) 7(8):585–98. doi: 10.1038/nrc2189
10. Di Marzo L, Desantis V, Solimando AG, Ruggieri S, Annese T, Nico B, et al. Microenvironment Drug Resistance in Multiple Myeloma: Emerging New Players. Oncotarget (2016) 7(37):60698–711. doi: 10.18632/oncotarget.10849
11. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-Specific Cell Surface Protein Tim-3 Regulates Macrophage Activation and Severity of an Autoimmune Disease. Nature (2002) 415(6871):536–41. doi: 10.1038/415536a
12. Janker L, Mayer RL, Bileck A, Kreutz D, Mader JC, Utpatel K, et al. Metabolic, Anti-Apoptotic and Immune Evasion Strategies of Primary Human Myeloma Cells Indicate Adaptations to Hypoxia. Mol Cell Proteomics (2019) 18(5):936–53. doi: 10.1074/mcp.RA119.001390
13. Guillerey C, Nakamura K, Vuckovic S, Hill GR, Smyth MJ. Immune Responses in Multiple Myeloma: Role of the Natural Immune Surveillance and Potential of Immunotherapies. Cell Mol Life Sci (2016) 73(8):1569–89. doi: 10.1007/s00018-016-2135-z
14. Benson DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, et al. The PD-1/PD-L1 Axis Modulates the Natural Killer Cell Versus Multiple Myeloma Effect: A Therapeutic Target for CT-011, a Novel Monoclonal Anti–PD-1 Antibody. Blood (2010) 116(13):2286–94. doi: 10.1182/blood-2010-02-271874
15. Allegra A, Innao V, Gerace D, Allegra AG, Vaddinelli D, Bianco O, et al. The Adipose Organ and Multiple Myeloma: {Impact} of Adipokines on Tumor Growth and Potential Sites for Therapeutic Intervention. Eur J Intern Med (2018) 53:12–20. doi: 10.1016/j.ejim.2018.05.033
16. Liu H, He J, Koh SP, Zhong Y, Liu Z, Wang Z, et al. Reprogrammed Marrow Adipocytes Contribute to Myeloma-Induced Bone Disease. Sci Transl Med (2019) 11:eaau9087. doi: 10.1126/scitranslmed.aau9087
17. Yavasoglu I, Tombuloglu M, Kadikoylu G, Donmez A, Cagirgan S, Bolaman Z. Cholesterol Levels in Patients With Multiple Myeloma. Ann Hematol (2008) 87:223–8. doi: 10.1007/s00277-007-0375-6
18. Liang L, Li J, Fu H, Liu X, Liu P. Identification of High Serum Apolipoprotein A1 as a Favorable Prognostic Indicator in Patients With Multiple Myeloma. J Cancer (2019) 10:4852–9. doi: 10.7150/jca.31357
19. Gozzetti A, Gennari L, Merlotti D, Salvadori S, De Paola V, Avanzati A, et al. The Effects of Zoledronic Acid on Serum Lipids in Multiple Myeloma Patients. Calcif Tissue Int (2008) 82(4):258–62. doi: 10.1007/s00223-008-9123-8
20. Heuck CJ, Mehta J, Bhagat T, Gundabolu K, Yu Y, Khan S, et al. Myeloma is Characterized by Stage-Specific Alterations in DNA Methylation That Occur Early During Myelomagenesis. J Immunol (2013) 190:2966–75. doi: 10.4049/jimmunol.120249
21. Lu L, Gao Y, Zhang Z, Cao Q, Zhang X, Zou J, et al. Kdm2a/B Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear Beta-Catenin. Dev Cell (2015) 33(6):660–74. doi: 10.1016/j.devcel.2015.04.006
22. Marsin AS, Bouzin C, Bertrand L, Hue L. The Stimulation of Glycolysis by Hypoxia in Activated Monocytes Is Mediated by AMP-Activated Protein Kinase and Inducible 6-Phosphofructo-2-Kinase. J Biol Chem (2002) 277(34):30778–83. doi: 10.1074/jbc.M205213200
23. Blade J, Fernandez de Larrea C, Rosinol L, Cibeira MT, Jimenez R, Powles R. Soft-Tissue Plasmacytomas in Multiple Myeloma: Incidence, Mechanisms of Extramedullary Spread, and Treatment Approach. J Clin Oncol (2011) 29(28):3805–12. doi: 10.1200/JCO.2011.34.9290
24. Usmani SZ, Heuck C, Mitchell A, Szymonifka J, Nair B, Hoering A, et al. Extramedullary Disease Portends Poor Prognosis in Multiple Myeloma and Is Over-Represented in High-Risk Disease Even in the Era of Novel Agents. Haematologica (2012) 97(11):1761–7. doi: 10.3324/haematol.2012.065698
Keywords: multiple myeloma, genetics of myeloma, extramedullary, biology, signaling
Citation: Gozzetti A, Kok CH and Li C-F (2022) Editorial: Molecular Mechanisms of Multiple Myeloma. Front. Oncol. 12:870123. doi: 10.3389/fonc.2022.870123
Received: 05 February 2022; Accepted: 18 February 2022;
Published: 10 March 2022.
Edited and reviewed by:
Alessandro Isidori, AORMN Hospital, ItalyCopyright © 2022 Gozzetti, Kok and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alessandro Gozzetti, Z296emV0dGlAdW5pc2kuaXQ=