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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, 2008; DOI 10.1182/blood-2007-07-099531. This Article Full Text 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 Citation Map 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 Google Scholar Articles by Gowda, A. Articles by Byrd, J. C. PubMed PubMed Citation Articles by Gowda, A. Articles by Byrd, J. C. Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 leukemia cells in vitro Aruna Gowda1, Julie Roda2, Syed-Rehan A. Hussain1, Asha Ramanunni1, Trupti Joshi2, Susan Schmidt1, Xiaoli Zhang3, Amy Lehman3, David Jarjoura3, William E. Carson4, Wayne Kindsvogel5, Carolyn Cheney1, Michael A. Caligiuri1, Susheela Tridandapani2, Natarajan Muthusamy1, and John C. Byrd1 1 Division of Hematology-Oncology, Department of Medicine; 2 Division of Pulmonary Medicine, Department of Medicine; 3 Center for Biostatistics; and 4 Department of Surgery, The Ohio State University, Columbus; and 5 ZymoGenetics, Seattle, WA Interleukin-21 (IL-21) is a recently identified -chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based on 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 chronic lymphocytic leukemia (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 proapoptotic BH3 domain protein BIM. IL-21–induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA 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 proapoptotic 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 end point 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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