Survival Response to B-Cell Receptor Ligation Is Restricted to Progressive Chronic Lymphocytic Leukemia Cells Irrespective of Zap70 Expression
(2006)
Journal - Cancer Research
Abstract :
Despite very similar gene expression profiles, the clinicalcourse of B-cell chronic lymphocytic leukemia (B-CLL) is heterogeneous.Immunoglobulin VH (IgVH) mutational status and expression ofB-cell receptor (BCR) signaling mediators have been associatedwith disease progression. However, the consequences of BCR engagementon cell survival and evolution of the disease remain unclear.We show here that B-CLL cell survival is dependent on the thresholdof BCR stimulation induced by immobilized antibody, in contrastto soluble anti-µ F(ab)'2 antibody, which leads to apoptosis.Measurement of metabolic activity and apoptotic response discriminatedtwo subgroups. "Nonresponders" showed low metabolic activityand unmodified apoptotic response upon BCR stimulation. In contrast,"responders" exhibited increased metabolic activity and inhibitionof spontaneous apoptosis. This survival advantage was associatedto a BCR-dependent activation profile leading to induction ofcyclin D2/cyclin-dependent kinase 4 (cdk4) expression and G1cell cycle progression. The ability to respond to BCR ligationcorrelated with an unfavorable clinical course and allowed todefine an additional group of patients among IgVH-mutated casesexhibiting a risk of progression. Remarkably, we show that Zap70expression was neither mandatory nor sufficient to generatedownstream survival signals and cyclin D2/cdk4 up-regulation.In conclusion, BCR engagement has a significant effect on B-CLLcell survival, activation, and G1 progression. Furthermore,our results provide new insights in the physiopathology of progressiveIgVH-mutated cases. (Cancer Res 2006; 66(14): 7158-66)