SEARCH:   Advanced

Blood, 30 April 2009, Vol. 113, No. 18, pp. 4300-4308. Prepublished online as a Blood First Edition Paper on February 3, 2009; DOI 10.1182/blood-2008-11-187708. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-11-187708v1 113/18/4300    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Secchiero, P. Articles by Zauli, G. Search for Related Content PubMed PubMed Citation Articles by Secchiero, P. Articles by Zauli, G. Related Collections Myeloid Neoplasia Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism Paola Secchiero1, Elisabetta Melloni1, Maria Grazia di Iasio1, Mario Tiribelli2, Erika Rimondi1, Federica Corallini1, Valter Gattei3, and Giorgio Zauli1 1 Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy; 2 Department of Medical and Morphological Research, Division of Hematology and Bone Marrow Transplantation, University Hospital, Udine, Italy; 3 Clinical and Experimental Hematology Research Unit, Centro di Riferimento Oncologico, Istituti di ricovero e cura a carattere scientifico (IRCCS), Aviano (PN), Italy The small molecule inhibitor of the MDM2/p53 interaction Nutlin-3 significantly up-regulated the steady-state mRNA and protein levels of Notch1 in TP53wild-type (OCI, SKW6.4) but not in TP53deleted (HL-60) or TP53mutated (BJAB) leukemic cell lines. A direct demonstration that NOTCH1 was a transcriptional target of p53 in leukemic cells was obtained in experiments carried out with siRNA for p53. Moreover, inhibition of Notch1 expression using Notch1-specific siRNA significantly increased cytotoxicity in TP53wild-type leukemic cells. Of note, Nutlin-3 up-regulated Notch1 expression also in primary TP53wild-type B-chronic lymphocytic leukemia (B-CLL) cells and the combined use of Nutlin-3 plus pharmacological -secretase inhibitors of the Notch signaling showed a synergistic cytotoxicity in both TP53wild-type leukemic cell lines and primary B-CLL cells. A potential drawback of -secretase inhibitors was their ability to enhance osteoclastic maturation of normal circulating preosteoclasts induced by RANKL + M-CSF. Notwithstanding, Nutlin-3 completely suppressed osteoclastogenesis irrespective of the presence of -secretase inhibitors. Taken together, these data indicate that the p53-dependent up-regulation of Notch1 in response to Nutlin-3 represents an antiapoptotic feedback mechanism able to restrain the potential therapeutic efficacy of Nutlin-3 in hematologic malignancies. Therefore, therapeutic combinations of Nutlin-3 + -secretase inhibitors might potentiate the cytotoxicity of Nutlin-3 in p53wild-type leukemic cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020