p57(Kip2) is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells

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 G(1) cell cycle arrest associated with the accumulation of p57(Kip2), a cyclin-dependent kinase inhibitor (CKI). Interestingly, p57(Kip2) increase precedes the reported STI571-dependent upregulation of p27(Kip1). A number of complementary approaches allow the demonstration that p57(Kip2) buildup is due to the transcriptional activation of CDKN1C, the p57(Kip2)-encoding gene, while neither p57(Kip2) half-life elongation nor its cell relocalization were observed. We also identified a heretofore undescribed pattern of p57(Kip2) phosphorylated isoforms which, however, did not change in response to STI571 cell treatment. The imatinib-dependent p57(Kip2) 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 p271(KiP1) level. Finally, CD34(+) cells from CML patients display a clear imatinib-dependent p57(Kip2) upregulation, which was not observed in CD34(+) cells from control subjects. In conclusion, our study points to p57(Kip2) as a novel and precocious effector of BCR-ABL targeting drugs.