Journal Article

p57<sup>Kip2</sup> is a downstream effector of BCR–ABL kinase inhibitors in chronic myelogenous leukemia cells

Adriana Borriello, Ilaria Caldarelli, Debora Bencivenga, Valeria Cucciolla, Adriana Oliva, Emilio Usala, Paolo Danise, Luisa Ronzoni, Silverio Perrotta and Fulvio Della Ragione

in Carcinogenesis

Volume 32, issue 1, pages 10-18
Published in print January 2011 | ISSN: 0143-3334
Published online October 2010 | e-ISSN: 1460-2180 | DOI:
p57Kip2 is a downstream effector of BCR–ABL kinase inhibitors in chronic myelogenous leukemia cells

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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, CD34+ cells from CML patients display a clear imatinib-dependent p57Kip2 upregulation, which was not observed in CD34+ cells from control subjects. In conclusion, our study points to p57Kip2 as a novel and precocious effector of BCR–ABL targeting drugs.

Journal Article.  6705 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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