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Blood, 1 July 2007, Vol. 110, No. 1, pp. 384-387. Prepublished online as a Blood First Edition Paper on March 21, 2007; DOI 10.1182/blood-2006-08-038398. This Article Full Text (PDF) All Versions of this Article: blood-2006-08-038398v1 110/1/384    most recent Alert me when this article is cited Alert me if a correction is posted 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 Troeger, A. Articles by Dilloo, D. Search for Related Content PubMed PubMed Citation Articles by Troeger, A. Articles by Dilloo, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 1, 2006 Accepted March 9, 2007 Upregulation of c-FLIPS+R upon CD40 stimulation is associated with inhibition of CD95-induced apoptosis in primary precursor B-ALL Anja Troeger*, Ingo Schmitz, Meinolf Siepermann, Ludmila Glouchkova, Ulrike Gerdemann, Gritta E. Janka-Schaub, Klaus Schulze-Osthoff, and Dagmar Dilloo Clinic for Pediatric Hematology, Oncology and Immunology, Heinrich Heine University of Duesseldorf, Duesseldorf, Germany Institute of Molecular Medicine, Heinrich Heine University of Duesseldorf, Duesseldorf, Germany Clinic for Pediatric Hematology and Oncology, University Hospital, Hamburg, Germany * Corresponding author; email: troeger{at}med.uni-duesseldorf.de. Previous studies on apoptosis defects in acute lymphoblastic leukemia (ALL) have focused on chemotherapy-induced, primarily mitochondrial death pathways. Yet, immunological surveillance mechanisms including sensitization to apoptotic signals mediated via the death receptor CD95 might contribute to leukemic control. Here, we show that primary B-cell precursor ALL cells from children escape from receptor-dependent cell death in two ways: Resting ALL blasts are protected from receptor-mediated apoptosis due to the absence of CD95 surface expression. However, even though CD40 ligation results in upregulation of CD95, ALL blasts, unlike normal B cells, remain resistant to apoptosis. We show that this apoptosis resistance involves the selective upregulation of the short isoforms of the caspase-8 inhibitor c-FLIP acting directly at the CD95 receptor level. Treatment with cycloheximide during CD40-activation prevents upregulation of those c-FLIP isoforms and sensitizes ALL cells towards CD95-mediated apoptosis. We therefore propose that induction of the short c-FLIP isoforms inhibits the onset of CD95-induced apoptosis in primary CD40-stimulated ALL cells despite high CD95 expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Troeger, L. Glouchkova, B. Ackermann, G. Escherich, R. Meisel, H. Hanenberg, M. L. den Boer, R. Pieters, G. E. Janka-Schaub, U. Goebel, et al. High expression of CD40 on B-cell precursor acute lymphoblastic leukemia blasts is an independent risk factor associated with improved survival and enhanced capacity to up-regulate the death receptor CD95 Blood, August 15, 2008; 112(4): 1028 - 1034. [Abstract] [Full Text] [PDF] M. Travert, P. Ame-Thomas, C. Pangault, A. Morizot, O. Micheau, G. Semana, T. Lamy, T. Fest, K. Tarte, and T. Guillaudeux CD40 Ligand Protects from TRAIL-Induced Apoptosis in Follicular Lymphomas through NF-{kappa}B Activation and Up-Regulation of c-FLIP and Bcl-xL J. Immunol., July 15, 2008; 181(2): 1001 - 1011. [Abstract] [Full Text] [PDF]

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