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IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop

Emmanuelle Ménoret^*, Sophie Maïga^*, Géraldine Descamps^*, Catherine Pellat-Deceunynck^*, Caroline Fraslon, Melania Cappellano, Philippe Moreau, Régis Bataille^* and Martine Amiot^1,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 892, Université de Nantes, Nantes Atlantique Universités, Unité de Formation et de Recherche, Médecine et Techniques Médicales, Nantes, France; Equipe 10 labélisée Ligue Nationale contre le Cancer 2008; Department of Clinical Haematology, CHU Hôtel-Dieu, Nantes France; and Sanofi-aventis, Oncology Therapeutic Department, 13 quai Jules Guesde, Vitry sur Seine, France

IL-21 is a member of the type I cytokine family related most closely to IL-2 and IL-15. IL-21 is a pleiotropic cytokine, produced by T, NKT, and dendritic cells, which modulates lymphoid and myeloid cell functions. Besides its activities on normal lymphoid cells, it has been shown that IL-21 is a growth factor for myeloma cells. In the present study, we demonstrate that IL-21 generated myeloma colonies from 9 of 24 human myeloma cell lines (HMCL) in a collagen-based assay. Of major interest, the capacity of IL-21 to stimulate clonogenicity was restricted to CD45^– HMCL. We found that IL-21 induced tyrosine phosphorylation of STAT-3, STAT-1, and Erk1/2. Interestingly, an Akt activation was observed lately after 30 min to 1 h of IL-21 stimulation, indicating that this Akt phosphorylation could be due to an IGF-1 autocrine loop. This hypothesis was sustained both by the fact that IL-21 treatment induced an IGF-1 mRNA synthesis and that an antagonistic anti-IGF-1 receptor mAb (AVE1642) strongly inhibits the IL-21-induced clonogenicity. Thus, we demonstrated by quantitative PCR that IL-21 induced clonogenicity through an autocrine IGF-1 secretion in HMCL and primary myeloma cells. Because we have previously demonstrated that CD45 phosphatase inhibits the IGF-1 signaling, this inhibitory effect of CD45 explains why the IL-21-induced clonogenicity was restricted to CD45^– HMCL. These results support that therapy against IGF-1R, which are presently under investigation in multiple myeloma, could be beneficial, not only to suppress IGF-1-mediated myeloma cell growth, but also IL-21-mediated myeloma cell growth.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Martine Amiot, Unité Mixte de Recherche 892, Département de Recherche en Cancérologie, 9, quai Moncousu, Nantes, France. E-mail address: mamiot{at}nantes.inserm.fr

² Abbreviations used in this paper: MM, multiple myeloma; HMCL, human myeloma cell line.