p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells

Abstract

Chronic myelogenous leukemia (CML) is characterized by the expression of BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show that BCR-ABL-positive CML cell lines treated with imatinib (STI571) undergo G1 cell cycle arrest associated with the accumulation of p57Kip2, a cyclin-dependent kinase inhibitor (CKI). Interestingly, p57Kip2 increase precedes the reported STI571-dependent upregulation of p27Kip1. A number of complementary approaches allow the demonstration that p57Kip2 buildup is due to the transcriptional activation of CDKN1C, the p57Kip2-encoding gene, while neither p57Kip2 half-life elongation nor its cell relocalization were observed.We also identified a heretofore undescribed pattern of p57Kip2 phosphorylated isoforms which, however, did not change in response to STI571 cell treatment. The imatinib-dependent p57Kip2 upregulation occurs only in STI571-responsive cells, while the CKI accumulation was not evidenced in an imatinib-resistant clone. Nilotinib and dasatinib (second-generation BCR-ABL inhibitors), at concentrations comparable to those used in therapy, increase the CKI but do not affect p27Kip1 level. Finally, CD341 cells from CML patients display a clear imatinib-dependent p57Kip2 upregulation, which was not observed in CD341 cells from control subjects. In conclusion, our study points to p57Kip2 as a novel and precocious effector of BCR-ABL targeting drugs. © The Author 2010. Published by Oxford University Press. All rights reserved.