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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3708-3715.
Prepublished online as a Blood First Edition Paper on January 3, 2006; DOI 10.1182/blood-2005-09-3535.
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NEOPLASIA
Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells
Daniela de Totero,
Raffaella Meazza,
Simona Zupo,
Giovanna Cutrona,
Serena Matis,
Monica Colombo,
Enrico Balleari,
Ivana Pierri,
Marina Fabbi,
Matteo Capaia,
Bruno Azzarone,
Marco Gobbi,
Manlio Ferrarini, and
Silvano Ferrini
From the Department of Translational Oncology and Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Istituto G. Gaslini, Clinical and Experimental Immunology, Genoa, Italy; Department of Hematology and Oncology, University of Genoa, Italy; and U542 Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Paul Brousse, Villejuif, France.
Interleukin-21 (IL-21) is a member of the IL-2 cytokine family, which mediates proliferation or growth arrest and apoptosis of normal B cells, depending on their activation state. Here we demonstrate that surface IL-21 receptor (R) is expressed at variable levels by chronic lymphocytic leukemia (CLL) B cells freshly isolated from 33 different patients. IL-21R expression was up-regulated following cell stimulation via surface CD40. Therefore, IL-21 effects were more evident in CD40-activated CLL B cells. IL-21 induced an early signaling cascade in CLL B cells, which included JAK-1 and JAK-3 autophosphorylation and tyrosine phosphorylation of STAT-1, STAT-3, and STAT-5. IL-21 signaling failed to stimulate CLL B-cell proliferation, but induced their apoptosis. In addition, IL-21 counteracted the proliferative and antiapoptotic signals delivered by IL-15 to CLL B cells. IL-21-mediated apoptosis involved activation of caspase-8 and caspase-3, cleavage of Bid to its active form t-Bid, and cleavage of PARP and of p27Kip-1. Recent data indicate that CLL B cells require interaction with the microenvironment for their survival and expansion. The present findings thus provide a set of new mechanisms involved in the balance between cell-survival and apoptotic signals in CLL B cells.
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