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Bone marrow stromal cell-fueled multiple myeloma growth and osteoclastogenesis are sustained by protein kinase CK2

Leukemia volume 28, pages 2094–2097 (2014)Cite this article

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Multiple myeloma (MM) is an incurable B-cell malignancy characterized by uncontrolled growth of clonal plasma cells.1 MM cells’ dwelling in the bone marrow (BM) niche is associated with alterations of the surrounding microenvironment, which confers resistance to cytotoxic noxae. These changes are partly sustained by delivery of growth signals from BM stromal cells (BMSCs) and perturbations affecting bone-remodeling mechanisms.2 Secretion of several growth factors/cytokines (that is, IL-6 and TNFα) promotes the evolution of the malignant clone(s). The NF-κB and JAK/STAT3 are among the most active signaling cascades triggered in malignant plasma cells.3, 4 Homing of MM cells to the BM niche are largely dependent on BMSC-secreted chemokine SDF1α/CXCL12 and its receptor CXCR4 on MM. Disruption of this circuit causes mobilization of MM cells outside the BM, loss of the protective niche and increased sensitivity to chemotherapy.5 Moreover, about 70% of MM patients present the MM-associated bone disease (MMABD) caused by derangements between bone resorption (osteoclast (OC) activity) and bone deposition (osteoblast activity) in the MM BM milieu.6

We and others have previously shown that protein kinase CK2 is an essential regulator of malignant plasma cell survival by impinging on NF-κB and STAT3 signaling, the endoplasmic reticulum stress/unfolded protein response and the sensitivity to classic and novel chemotherapeutics.7, 8, 9 CK2 can stimulate NF-κB by direct phosphorylation of Ser529 on p65/RelA.10 CK2 activation of STAT3 signaling can result from triggering of upstream JAK kinases and/or direct phosphorylation of Ser727.11 Remarkably, the oral adenosine 5′-triphosphate-competitive small CK2 inhibitor CX-4945 has entered phase I clinical trials in the USA in solid tumors and MM12 and displayed activity also against other B-cell tumors.13 Although CK2 was demonstrated to protect malignant plasma cells from apoptosis-inducing noxae, its role in the MM–BMSC–OC cross-talk was never investigated, nor was its function in osteoclastogenesis/osteoblasts.

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Acknowledgements

We thank patients and their families for accepting to donate samples. We thank Dr C Gattazzo and Dr B Molon (Venetian Institute of Molecular Medicine) for helping with chemotaxis experiments. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (n. 14481), from the Italian Ministry of Education, University and Research (FIRB—Futuro in Ricerca 2008, n. RBFR086EW9_001) and from the University of Padua (Progetti di Ricerca di Ateneo n. CPDA114940/11) to FP.

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Authors and Affiliations

  1. Department of Medicine, Hematology and Clinical Immunology Branch, University of Padua, Padua, Italy

    S Manni, E Mandato, A Brancalion, L Quotti Tubi, P Macaccaro, F Adami, R Zambello, C Gurrieri, G Semenzato & F Piazza

  2. Venetian Institute of Molecular Medicine, Padua, Italy

    S Manni, E Mandato, A Brancalion, L Quotti Tubi, P Macaccaro, A Cabrelle, R Zambello, C Gurrieri, G Semenzato & F Piazza

  3. Department of Clinical and Experimental Medicine, Hematology, University of Parma, Parma, Italy

    D Toscani & N Giuliani

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  1. S Manni
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  2. D Toscani
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Correspondence to F Piazza.

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Author contributions

SM performed the research, analyzed the data and wrote the manuscript. DT, EM, AB, LQT, PC, AC and PM performed the research and analyzed the data; FA, RZ and CG contributed patients’ samples and critical advices during elaboration of the data; NG contributed samples and reagents, and designed the experiments; GS contributed patients, advices and edited the manuscript; FP conceived and designed the study, provided funding, supervised the research and data analysis, and wrote the manuscript.

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Manni, S., Toscani, D., Mandato, E. et al. Bone marrow stromal cell-fueled multiple myeloma growth and osteoclastogenesis are sustained by protein kinase CK2. Leukemia 28, 2094–2097 (2014). https://doi.org/10.1038/leu.2014.178

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