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Blood, 22 January 2009, Vol. 113, No. 4, pp. 856-865.
Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2008-02-139725.
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Submitted February 19, 2008
Accepted August 12, 2008
Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells
Emanuela Rosati, Rita Sabatini, Giuliana Rampino, Antonio Tabilio, Mauro Di Ianni, Katia Fettucciari, Andrea Bartoli, Stefano Coaccioli, Isabella Screpanti, and Pierfrancesco Marconi*
Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy
Department of Internal Medicine and Rheumatology Unit, University of Perugia, Didactic and Scientific Division of Terni, Perugia, Italy
Department of Experimental Medicine, University "La Sapienza", Roma, Italy
* Corresponding author; email: marimmun{at}unipg.it.
Notch signaling is involved in tumorigenesis but its role in B-chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells and its activation is further increased in B-CLL cells which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased NF- B activity, c-IAP2 and XIAP expression. In contrast, Notch signaling inhibition by the  -secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering-RNA (siRNA) accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-B activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target.
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