Bioactivity and Prognostic Significance of Growth Differentiation Factor GDF15 Secreted by Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma
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- Jill Corre
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Elodie Labat
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Nicolas Espagnolle
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Benjamin Hébraud
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Hervé Avet-Loiseau
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Murielle Roussel
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Anne Huynh
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Mélanie Gadelorge
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Pierre Cordelier
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Bernard Klein
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Philippe Moreau
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Thierry Facon
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Jean-Jacques Fournié
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Michel Attal
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
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- Philippe Bourin
- Authors' Affiliations: 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1037; 2Hematology Laboratory, University Hospital Purpan, Toulouse; 3Intergroupe Francophone du Myélome (IFM); 4STROMALab; 5Hematology Department, University Hospital Purpan; 6CSA21, Toulouse; 7Hematology Laboratory and 8Hematology Department, University Hospital Hôtel-Dieu, Nantes; 9INSERM U847, Institute of Research in Biotherapy, Montpellier; and 10Hematology Department, University Hospital Huriez, Lille, France
説明
<jats:title>Abstract</jats:title> <jats:p>Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival. Cancer Res; 72(6); 1395–406. ©2012 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 72 (6), 1395-1406, 2012-03-14
American Association for Cancer Research (AACR)