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 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.
Troeger
Anja
A
Clinic for Pediatric Hematology, Heinrich Heine University of Duesseldorf, Germany. troeger@med.uni-duesseldorf.de
Schmitz
Ingo
I
Siepermann
Meinolf
M
Glouchkova
Ludmila
L
Gerdemann
Ulrike
U
Janka-Schaub
Gritta E
GE
Schulze-Osthoff
Klaus
K
Dilloo
Dagmar
D
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D019013:CD40 Antigens / Q000502:physiology*; D006801:Humans; D007157:Immunologic Surveillance; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000473:pathology*; D020033:Protein Isoforms; D015854:Up-Regulation; D019014:fas Receptor / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019013:CD40 Antigens; C506386:CFLAR protein, human; D020033:Protein Isoforms; D019014:fas Receptor