IL-21 Mediates Pro-Apoptic Signals in CLL Cells

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Blood First Edition Paper, prepublished online January 3, 2006PubMed

Submitted September 1, 2005

Accepted December 27, 2005

Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering

and mediates pro-apoptotic signals in chronic lymphocytic leukemia B

cells

a de Totero, Raffaella Meazza, Simona Zupo, Giovanna Cutrona,

Serena Matis, Colombo, Enrico Balleari, Ivana Pierri, Marina

Fabbi, Matteo Capaia, Bruno Azzarone, Marco Gobbi, Manlio Ferrarini,

and Silvano Ferrini*

Dept. of Translational Oncology and Medical Oncology C, Istituto

Nazionale per la Ricerca sul Cancro, Genoa, Italy

Clinical and Experimental Immunology, Istituto G. Gaslini, Genoa,

Italy

Dept. of Hematology and Oncology, University of Genoa, Genoa, Italy

Hematology and Oncology, University of Genoa, Genoa, Italy

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-21R is expressed at variable levels by 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 signalling cascade in CLL B cells, which

included Jak-1 and 3 auto-phosphorylation and tyrosine

phosphorylation of STAT-1, -3 and 5. IL-21 signalling failed to

stimulate CLL B cell proliferation, but induced their apoptosis. In

addition, IL-21 counteracted the proliferative and anti-apoptotic

signals delivered by IL-15 to CLL B cells.

IL-21-mediated apoptosis involved activation of caspase-8 and 3,

cleavage of Bid to its active form t-Bid, and cleavage of PARP and of

p27/Kip-1.

Recent data indicate that CLL B cells require interaction with the

micoenvironment 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.