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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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NEOPLASIA
Brief Report
Up-regulation of c-FLIPS+R upon CD40 stimulation is associated with inhibition of CD95-induced apoptosis in primary precursor B-ALL
Anja Troeger1,
Ingo Schmitz2,
Meinolf Siepermann1,
Ludmila Glouchkova1,
Ulrike Gerdemann1,
Gritta E. Janka-Schaub3,
Klaus Schulze-Osthoff2, and
Dagmar Dilloo1
1 Clinic for Pediatric Hematology, Oncology and Immunology;
2 Institute of Molecular Medicine, Heinrich Heine University of Duesseldorf, Germany;
3 Clinic for Pediatric Hematology and Oncology, University Hospital, Hamburg, Germany
Previous studies on apoptosis defects in acute lymphoblastic leukemia (ALL) have focused on chemotherapy-induced, primarily mitochondrial death pathways. Yet, immunologic 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 2 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 up-regulation of CD95, ALL blasts, unlike normal B cells, remain resistant to apoptosis. We show that this apoptosis resistance involves the selective up-regulation 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 up-regulation of those c-FLIP isoforms and sensitizes ALL cells toward 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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