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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.
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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.
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