Downregulation of the CD95 receptor and defect CD40-mediated signal transduction in B-chronic lymphocytic leukemia cells.
Cross-linking of the CD40 receptors has been shown to induce protein tyrosine kinases (PTK) phosphorylation and prevent apoptosis in Bcl-2 negative germinal center B cells. The expression of CD40 on B chronic lymphocytic leukemia (B-CLL) cells was found to be similar to that of normal B cells. Activation of normal B cells with soluble anti-CD40 monoclonal antibody (mAb) induced tyrosine phosphorylation, prolonged survival and prevented apoptosis. However, activation of CD40 on B-CLL cells using soluble anti-CD40 mAb does not influence survival or apoptosis. Normal B cells entered apoptosis when cultured in the presence of soluble anti-CD95 mAb. This process was independent of PTK activity. On B-CLL cells, the CD95 molecules were downregulated and a transient PTK signal was observed when cross-linking of the receptor by soluble anti-CD95 mAb occurred. Interestingly, B-CLL cells did not enter apoptosis in the presence of anti-CD95 mAb. Our study indicates that survival signals mediated through the CD40 molecule and death signals mediated through the CD95 molecule used different intracellular pathways in control donor B cells. In contrast, B-CLL cells do not respond to these signals. The leukemic B cells showed a defective CD40-mediated signal transduction and downregulated CD95 receptor expression. As a consequence, no apoptosis could be induced in B-CLL cells by a soluble anti-CD95 mAb. The abnormalities of these receptors may contribute to the long-lived status of B-CLL cells.
Laytragoon-Lewin
N
N
Department of Experimental Oncology, Uppsala University, Stockholm, Sweden. Nongnit.Lewin@cck.ki.se
Duhony
E
E
Bai
X F
XF
Mellstedt
H
H
D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D015536:Down-Regulation; D053222:Fas Ligand Protein; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology*
D019013:CD40 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor