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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4888-4897.
Prepublished online as a Blood First Edition Paper on February 23, 2006; DOI 10.1182/blood-2005-08-3399.
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Submitted August 22, 2005
Accepted February 8, 2006
A common phosphotyrosine signature for the Bcr-Abl kinase
Valerie L Goss, Kimberly A Lee, Albrecht Moritz, Julie Nardone, Erik J Spek, Joan MacNeill, John Rush, Michael J Comb, and Roberto D Polakiewicz*
Cell Signaling Technology, Inc., Danvers, MA, USA
* Corresponding author; email: rpolakiewicz{at}cellsignal.com.
The Bcr-Abl fusion kinase drives oncogenesis in chronic myeloid leukemia (CML). CML patients are currently treated with the Abl tyrosine kinase inhibitor imatinib, which is effective in early stages of the disease. However, resistance to imatinib arises in later disease stages due mainly to mutation of Bcr-Abl. To gain a deeper insight into Bcr-Abl signaling pathways we have generated phosphotyrosine profiles for six cell lines that represent three Bcr-Abl fusion types by using immunoaffinity purification of tyrosine phosphopeptides followed by tandem mass spectrometry. We identified 188 non-redundant tyrosine phosphorylated sites, 77 of which are novel. By comparing the profiles, we found a number of phosphotyrosine sites that are common to the six cell lines regardless of cellular background and fusion type, several of which are decreased by imatinib treatment. Comparison of this Bcr-Abl signature with the profile of cells expressing an alternative imatinib-sensitive fusion kinase, FIP1L1-PDGFRa revealed that these kinases signal through different pathways. This phosphoproteomic study of the Bcr-Abl fusion kinase highlights novel disease markers and potential drug-responsive biomarkers and adds novel insights into the oncogenic signals driven by the Bcr-Abl kinase.
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