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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-02-139725v1 113/4/856    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rosati, E. Articles by Marconi, P. Search for Related Content PubMed PubMed Citation Articles by Rosati, E. Articles by Marconi, P. Related Collections Lymphoid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells Emanuela Rosati1, Rita Sabatini1,*, Giuliana Rampino1,*, Antonio Tabilio2, Mauro Di Ianni2, Katia Fettucciari1, Andrea Bartoli1, Stefano Coaccioli3, Isabella Screpanti4, and Pierfrancesco Marconi1 1 Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia; 2 Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila; 3 Didactic and Scientific Division of Terni, Department of Internal Medicine and Rheumatology Unit, University of Perugia, Perugia; and 4 Department of Experimental Medicine, University La Sapienza, Rome, Italy 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 nuclear factor–kappa B (NF-B) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein (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 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: B-CLL kicks it up a Notch Barbara A. Osborne Blood 2009 113: 765-766. [Full Text] [PDF] This article has been cited by other articles: P. Secchiero, E. Melloni, M. G. di Iasio, M. Tiribelli, E. Rimondi, F. Corallini, V. Gattei, and G. Zauli Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism Blood, April 30, 2009; 113(18): 4300 - 4308. [Abstract] [Full Text] [PDF]

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