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CCR10/CCL27 crosstalk contributes to failure of proteasome-inhibitors in multiple myeloma

S. Thangavadivel, C. Zelle-Rieser, A. Olivier, B. Postert, G. Untergasser, J. Kern, A. Brunner, E. Gunsilius, R. Biedermann, R. Hajek, L. Pour, W. Willenbacher, R. Greil, K. Jöhrer,

. 2016 ; 7 (48) : 78605-78618.

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc18010995

The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.

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$a The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.
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$a Zelle-Rieser, Claudia $u Tyrolean Cancer Research Institute, Innsbruck, Austria.
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$a Olivier, Angelika $u Tyrolean Cancer Research Institute, Innsbruck, Austria.
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$a Postert, Benno $u Tyrolean Cancer Research Institute, Innsbruck, Austria.
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$a Untergasser, Gerold $u Tyrolean Cancer Research Institute, Innsbruck, Austria. Laboratory of Tumor Angiogenesis and Tumorbiology, Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
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$a Kern, Johann $u Laboratory of Tumor Angiogenesis and Tumorbiology, Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
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$a Brunner, Andrea $u Department of Pathology, Medical University Innsbruck, Innsbruck, Austria.
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$a Gunsilius, Eberhard $u Laboratory of Tumor Angiogenesis and Tumorbiology, Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
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$a Biedermann, Rainer $u Department of Orthopedic Surgery, Medical University Innsbruck, Innsbruck, Austria.
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$a Hajek, Roman $u Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic. Department of Hematooncology, Faculty of Medicine, University of Ostrava and University Hospital Ostrava, Ostrava, Czech Republic.
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$a Pour, Ludek $u Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic. Department of Hematooncology, Faculty of Medicine, University of Ostrava and University Hospital Ostrava, Ostrava, Czech Republic.
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$a Willenbacher, Wolfgang $u Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria.
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$a Greil, Richard $u Tyrolean Cancer Research Institute, Innsbruck, Austria. Salzburg Cancer Research Institute-Laboratory of Immunological and Molecular Cancer Research, Salzburg, Austria. Third Medical Department at The Paracelsus Medical University Salzburg, Austria. Cancer Cluster Salzburg (CCS), Salzburg, Austria.
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$a Jöhrer, Karin $u Tyrolean Cancer Research Institute, Innsbruck, Austria.
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