Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Cancers, vol. 13, pp. 1454

Abstract

Background. Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment. Methods: We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers. Results: Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p ≤ 0.02), in association with lower blood counts of recently-produced CD62L+ cMo in SMM (p = 0.004) and of all subsets of (CD62L+, CD62L− and FcεRI+) cMo in MM (p ≤ 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (p ≤ 0.03), SMM (p ≤ 0.03) and MM (p ≤ 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1β were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of FcεRI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1β and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro-inflammatory-high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory FcεRI+ cMo-, typical of MM presenting with bone lesions. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis.

Authors 17

1. Daniela Damasceno

   Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

2. Júlia Almeida

   Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

3. Cristina Teodósio Aachen Department of Immunology

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands

4. Luzalba Sanoja-Flores

   Consejo Superior de Investigaciones Científicas · Instituto de Biomedicina de Sevilla · Hospital Universitario Virgen del Rocío · Centro de Investigación Biomédica en Red de Cáncer · Universidad de Sevilla

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Institute of Biomedicine of Seville, Department of Hematology, University Hospital Virgen del Rocío of the Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, 41013 Seville, Spain

5. Andrea Mayado

   Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

6. Alba Pérez‐Pons

   Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

7. Noemí Puig

   Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación Biomédica en Red de Cáncer

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Service of Hematology, University Hospital of Salamanca (CAUSA) and IBSAL, 37007 Salamanca, Spain

8. Paula Arana

   BioCruces Health research Institute · Hospital de Cruces

   Affiliation as printed

   Regulation of the Immune System Group, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Plaza de Cruces 12, 48903 Barakaldo, Spain

9. Bruno Paiva

   Navarre Institute of Health Research · Clinica Universidad de Navarra · Centro de Investigación Biomédica en Red de Cáncer · Centro de Investigación Médica Aplicada

   Affiliation as printed

   Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

   Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), Clinica Universidad de Navarra, 31008 Pamplona, Spain

10. Fernando Solano

    Hospital General Nuestra Señora del Prado

    Affiliation as printed

    Hematology Service, Hospital Nuestra Señora del Prado, Talavera de la Reina, 45600 Toledo, Spain

11. Alfonso E. Romero

    Gerencia Regional de Salud de Castilla y León (Sacyl)

    Affiliation as printed

    Primary Health Care Center “Miguel Armijo”, Primary Health Care of Salamanca, Conserjería de Sanidad de Castilla y León (SACYL), 37007 Salamanca, Spain

12. Sergio Matarraz

    Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

    Affiliation as printed

    Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

    Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

13. Wouter B. L. van den Bossche Aachen Department of Immunology

    Leiden University Medical Center · Erasmus MC

    Affiliation as printed

    Department of Immunology, Erasmus University Medical Center, 3015 GA Rotterdam, The Netherlands

    Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands

14. Juan A Flores-Montero

    Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

    Affiliation as printed

    Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

    Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

15. Brian G.M. Durie

    Cedars-Sinai Medical Center

    Affiliation as printed

    Centro del Cáncer Cedars-Sinai Samuel Oschin, Los Angeles, CA 90048, USA

16. Jacques J. M. van Dongen Aachen Department of Immunology

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands

17. Alberto Órfão

    Consejo Superior de Investigaciones Científicas · Universidad de Salamanca · Instituto de Investigación Biomédica de Salamanca · Centro de Investigación del Cáncer · Centro de Investigación Biomédica en Red de Cáncer · Instituto de Biología Molecular y Celular del Cáncer de Salamanca

    Affiliation as printed

    Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain

    Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain