Sign up for Table of Contents Alerts.
Email this page
Print this page
Report
Regulation and Targeting of Eg5, a Mitotic Motor Protein in Blast Crisis CML: Overcoming Imatinib Resistance
Bing Z. Carter, Duncan H. Mak, Yuexi Shi, Wendy D. Schober, Rui-Yu Wang, Marina Konopleva, Erich Koller, Nicholas M. Dean and Michael Andreeff
volume 5 | issue 19
1 october 2006Pages: 2223 - 2229
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.
Patients with blast crisis (BC) CML frequently become resistant to Imatinib, a Bcr-Abl tyrosine kinase-targeting agent. Eg5, a microtubule-associated motor protein has been described to be highly expressed in BC CML by microarray analysis (Nowicki et al, Oncogene 22:3952-3963, 2003). We investigated the regulation of Eg5 by Bcr-Abl tyrosine kinase and its potential as a therapeutic target in BC CML. Eg5 was highly expressed in all Philadelphia chromosome positive (Ph+) cell lines and BC CML patient samples. Inhibition of Bcr-Abl by Imatinib downregulated Eg5 expression in Imatinibsensitive KBM5 and HL-60p185 cells, but not in Imatinib-resistant KBM5-STI571, harboring a T315I mutation, and Bcr-Abl-negative HL-60 cells. Blocking Eg5 expression with antisense oligonucleotide (Eg5-ASO) or inhibiting its activity with the smallmolecule Eg5 inhibitor, S-trityl-L-cysteine induced G2/M cell cycle block and subsequent cell death in both Imatinib-sensitive and -resistant cells. Further, Eg5-ASO treatment of SCID mice harboring KBM5 cell xenografts significantly prolonged the median survival of the animals (p=0.03). Our findings suggest that Eg5 is downstream of and regulated by Bcr-Abl tyrosine kinase in Philadelphia chromosome positive cells. Inhibition of Eg5 expression or its activity blocks cell cycle progression and induces cell death independent of the cellular response to Imatinib. Therefore, Eg5 could be a potential therapeutic target for the treatment of BC CML, in particular Imatinib-resistant BC CML.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.