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 Blood, 15 January 2008, Vol. 111, No. 2, pp. 517-524.
Prepublished online as a Blood First Edition Paper on October 15, 2007; DOI 10.1182/blood-2007-04-087882.

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CHEMOKINES, CYTOKINES, AND INTERLEUKINS

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Daniela de Totero1, Raffaella Meazza2, Matteo Capaia1, Marina Fabbi1, Bruno Azzarone3, Enrico Balleari4, Marco Gobbi4, Giovanna Cutrona1, Manlio Ferrarini1, and Silvano Ferrini1

1 Department of Translational Oncology and Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 2 Istituto G. Gaslini, Clinical and Experimental Immunology, Genoa, Italy; 3 U542 Inserm, Hopital Paul Brousse, Villejuif, France; 4 Department of Hematology and Oncology, University of Genoa, Genoa, Italy

The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common {gamma} chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and prevented apoptosis induced by surface IgM cross-linking. These effects were more evident in cells stimulated via surface CD40, which exhibited increased cell expression of IL-15R{alpha} chain and, in some of the cases, also of IL-2Rβ. IL-21 failed to induce CLL cell proliferation and instead promoted apoptosis. Following cell exposure to IL-15, phosphorylation of STAT5 was predominantly observed, whereas, following stimulation with IL-21, there was predominant STAT1 and STAT3 activation. Moreover, IL-15 but not IL-21 caused an increased phosphorylation of Shc and ERK1/2. Pharmacological inhibition of JAK3 or of MEK, which phosphorylates ERK1/2, efficiently blocked IL-15–induced CLL cell proliferation and the antiapoptotic effect of this cytokine. The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention.


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