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Myeloma

Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1

Leukemia volume 27, pages 1558–1566 (2013)Cite this article

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Abstract

Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF-1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch-targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels.

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Acknowledgements

We thank Prof Carmelo Carlo-Stella (Università degli Studi, Department of Medical Biotechnology and Translational Medicine) for providing MM cell lines, Prof M Cattaneo, A Gorio, E Faioni and Dr E Lesma (Università degli Studi di Milano, Department of Health Sciences) for equipment support.

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  1. L Mirandola, L Apicella, M Chiriva-Internati and R Chiaramonte: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Health Sciences, Università degli Studi di Milano, Milan, Italy

    L Mirandola, L Apicella, M Colombo, D G Berta, N Platonova, E Lazzari, M Lancellotti & R Chiaramonte

  2. Division of Hematology and Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, TX, USA

    Y Yu, E Cobos & M Chiriva-Internati

  3. Department of Health Sciences, Unit of Human Pathology, Università degli Studi di Milano, San Paolo Hospital Medical School, Milan, Italy

    G Bulfamante

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Mirandola, L., Apicella, L., Colombo, M. et al. Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1. Leukemia 27, 1558–1566 (2013). https://doi.org/10.1038/leu.2013.27

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