Up-regulation of c-FLIPS+R upon CD40 stimulation is associated with inhibition of CD95-induced apoptosis in primary precursor B-ALL

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 leu...

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Bibliographic Details
Published in:Blood 2007-07, Vol.110 (1), p.384-387
Main Authors: Troeger, Anja, Schmitz, Ingo, Siepermann, Meinolf, Glouchkova, Ludmila, Gerdemann, Ulrike, Janka-Schaub, Gritta E., Schulze-Osthoff, Klaus, Dilloo, Dagmar
Format: Article
Language:English
Subjects:
Apoptosis
Biological and medical sciences
CASP8 and FADD-Like Apoptosis Regulating Protein - genetics
CD40 Antigens - physiology
fas Receptor - physiology
Hematologic and hematopoietic diseases
Humans
Immunologic Surveillance
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - etiology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Protein Isoforms
Up-Regulation
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2006-08-038398