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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4723-4730. Prepublished online as a Blood First Edition Paper on January 11, 2008January 8, 2008; DOI 10.1182/blood-2007-07-099531. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-099531v1 blood-2007-07-099531v2 111/9/4723    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gowda, A. Articles by Byrd, J. C. Search for Related Content PubMed PubMed Citation Articles by Gowda, A. Articles by Byrd, J. C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 20, 2007 Accepted November 30, 2007 IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody dependent cellular cytotoxicity in primary chronic lymphocytic cells Aruna Gowda, Julie Roda, Rehan S Hussain, Asha Ramanunni, Trupti Joshi, Susan Schmidt, Xiaoli Zhang, Amy Lehman, David Jarjoura, Wayne Kindsvogel, Carolyn Cheney, Michael A. Caligiuri, Susheela Tridandapani, William E. Carson, Natarajan Muthusamy, and John C. Byrd* Division of Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, OH Division of Pulmonary Medicine, Department of Medicine, The Ohio State University, Columbus, OH Center for Biostatistics, The Ohio State University, Columbus, OH ZymoGenetics, Inc., Seattle, WA Department of Surgery, The Ohio State University, Columbus, OH * Corresponding author; email: john.byrd{at}osumc.edu. IL-21 is a recently identified gamma chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based upon this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune mediated clearance of the CLL cells. Our studies demonstrate that the majority of CLL patients have surface IL-21 receptor- and its expression correlates with apoptosis, tyrosine phosphorylation of STAT1, and up-regulation of the pro-apoptotic BH3 domain protein BIM. IL-21 induced BIM up regulation is critical for apoptosis as inhibition of BIM expression using SiRNA prevented IL-21 induced apoptosis. IL-21 treatment of CLL cells but not normal T-cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies. In addition to its pro-apoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody dependent cellular cytotoxicity against rituximab coated CLL cells in vitro. These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic endpoint to measure biologic effect of this cytokine in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: IL-21 as new therapy for CLL? Jean-Pierre Kolb Blood 2008 111: 4424-4425. [Full Text] [PDF]

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