Fludarabine-induced apoptosis of B chronic lymphocytic leukemia cells includes early cleavage of p27kip1 by caspases

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of growth arrested clonal B lymphocytes that undergo Apoptosis when treated with fludarabine. To further explore the mechanism for the cell cycle arrest, we examined the expression and activity of cyclin-dependent kinases and inhibitors in primary B-CLL cells. We observed high levels of p27kip1, cyclin D2, cyclin E, CDK2, and CDK4 expression in freshly isolated B-CLL cells. Despite high levels of cyclins and cdks, little CDK2 or CDK4 activity was observed with p27kip1 in complex with cyclinD2/CDK4 and cyclin E/CDK2. Remarkably, when B-CLL cells were treated in vitro with fludarabine, p27kip1 underwent caspase-specific degradation accompanied by an increase in CDK4 activity. We conclude that the G0/G1 arrest of B-CLL cells may protect against Apoptosis and that the decrease in p27kip1 expression by Caspase cleavage may be a key step in chemotherapy-induced Apoptosis in B-CLL.