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Myelodysplastic syndrome

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

Leukemia volume 29, pages 1901–1908 (2015)Cite this article

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Abstract

Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16+ mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16− Elastase+ myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM.

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Acknowledgements

This work was supported by the Henri Dubois Ferrière/Dinu Lipatti Foundation, the Swiss National Science Foundation, the Leenaards Foundation, the Swiss Cancer League, the Jacques and Gloria Gossweiller stiftung, the INSERM and the University Joseph Fourier. We thank Patrice Marche for its critical reading of the manuscript.

Author Contributions

IDS, BM and BH performed the experiments. TM, JP, TMK, SP and BH provided reagents and/or analyzed the data. TM and BH 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. Department of Pathology, Medicine Faculty, Geneva, Switzerland

    T McKee

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

    I Dunand-Sauthier

  4. Analytical Immunology of Chronic Pathologies, INSERMU823/University Joseph Fourier, Albert Bonniot Institute, La Tronche, France

    B Manfroi & B Huard

  5. Hematology, University Hospital, Grenoble, France

    S Park

  6. Hematology, University Hospital, Basel, Switzerland

    J Passweg

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Correspondence to B Huard.

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Matthes, T., McKee, T., Dunand-Sauthier, I. et al. Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow. Leukemia 29, 1901–1908 (2015). https://doi.org/10.1038/leu.2015.68

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