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Molecular and Cellular Biology, August 2006, p. 6082-6093, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02202-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Kinase Domain Mutants of Bcr-Abl Exhibit Altered Transformation Potency, Kinase Activity, and Substrate Utilization, Irrespective of Sensitivity to Imatinib{ddagger}

Ian J. Griswold,1,3,{dagger} Mary MacPartlin,1,{dagger} Thomas Bumm,1 Valerie L. Goss,4 Thomas O'Hare,1,3 Kimberly A. Lee,4 Amie S. Corbin,1,3 Eric P. Stoffregen,1 Caitlyn Smith,1 Kara Johnson,1 Erika M. Moseson,1,§ Lisa J. Wood,2 Roberto D. Polakiewicz,4 Brian J. Druker,1,3 and Michael W. Deininger1*

Center for Hematologic Malignancies, Oregon Health and Science University Cancer Institute,1 Oregon Health and Science University School of Nursing,2 Howard Hughes Medical Institute, 3181 S.W. Sam Jackson Park Rd., Portland, Oregon 97239-3098,3 Cell Signaling Technology, Inc., 166B Cummings Center, Beverly, Massachusetts 019154

Received 14 November 2005/ Returned for modification 23 January 2006/ Accepted 8 May 2006

Kinase domain (KD) mutations of Bcr-Abl interfering with imatinib binding are the major mechanism of acquired imatinib resistance in patients with Philadelphia chromosome-positive leukemia. Mutations of the ATP binding loop (p-loop) have been associated with a poor prognosis. We compared the transformation potency of five common KD mutants in various biological assays. Relative to unmutated (native) Bcr-Abl, the ATP binding loop mutants Y253F and E255K exhibited increased transformation potency, M351T and H396P were less potent, and the performance of T315I was assay dependent. The transformation potency of Y253F and M351T correlated with intrinsic Bcr-Abl kinase activity, whereas the kinase activity of E255K, H396P, and T315I did not correlate with transforming capabilities, suggesting that additional factors influence transformation potency. Analysis of the phosphotyrosine proteome by mass spectroscopy showed differential phosphorylation among the mutants, a finding consistent with altered substrate specificity and pathway activation. Mutations in the KD of Bcr-Abl influence kinase activity and signaling in a complex fashion, leading to gain- or loss-of-function variants. The drug resistance and transformation potency of mutants may determine the outcome of patients on therapy with Abl kinase inhibitors.

* Corresponding author. Mailing address: Center for Hematologic Malignancies, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098. Phone: (503) 494-1603. Fax: (503) 494-3688. E-mail: deininge{at}ohsu.edu.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} I.J.G. and M.M. contributed equally to this study.

§ Present address: Columbia University, College of Physicians and Surgeons, 630 West 168 St., New York, NY 10032.

Molecular and Cellular Biology, August 2006, p. 6082-6093, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02202-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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