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Multiple Myeloma

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

Leukemia volume 29, pages 1882–1890 (2015)Cite this article

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Abstract

Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor cells.

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Acknowledgements

This work was supported by the Henri Dubois Ferrière/Dinu Lipatti Foundation, the Swiss Cancer League, the INSERM and the Grenoble-Alpes University. We thank Patrice Marche for his critical reading of the manuscript.

Author contributions

ID-S, AZ, BM and BH performed experiments. TM and BB provided reagents. TM and BH analyzed data and wrote the manuscript. BH designed the study.

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Authors and Affiliations

  1. Division of Hematology, University Hospitals, Geneva, Switzerland

    T Matthes & B Huard

  2. Analytical Immunology for chronic pathologies, Albert Bonniot Institute, INSERM/University Joseph Fourier, Grenoble, France

    B Manfroi & B Huard

  3. Department of Pathology and Immunology, Medicine Faculty, Geneva, Switzerland

    A Zeller, I Dunand-Sauthier & B Huard

  4. Institute for Immunology, University Hospital, Oslo, Norway

    B Bogen

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  1. T Matthes
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Correspondence to B Huard.

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Matthes, T., Manfroi, B., Zeller, A. et al. Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow. Leukemia 29, 1882–1890 (2015). https://doi.org/10.1038/leu.2015.145

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