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

Abstract

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.

Prognostic impact of p27KIP1 expression in cyclin D1 positive lymphoproliferative disorders

“…34,35 Conversely, in CLL, we have shown previously that p27 expression was high and related to defective apoptosis. 36,51 In the present study, we demonstrated that p27 expression was the stronger survival predictor of all tested parameters. Distribution of p27 level of expression easily identified two distinct subgroups.…”

High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease

“…27 Therefore, we examined its expression at the mRNA level in the 3 isolated subpopulations. Semiquantitative RT-PCR results show a high expression of p27 ϪKip1 in the IgM ϩ isolated subset; whereas no, or very weak, expression was found in both IgG ϩ and IgM ϩ /IgG ϩ isolated subpopulations ( Figure 3D).…”

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

“…1,2,5,6 As a consequence, these cells display a resting phenotype, often respond poorly to activation and are mostly in G0/early G1 phase of the cell cycle, 7-9 a characteristic that may protect them from drugs-and activationinduced apoptosis. 10 CLL cells have been considered as anergic although this may be especially true for those with mutated IgV genes. CLL B cells have membrane markers of mature antigen-experienced cells.…”