BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib

Blood - Tập 116 - Trang 3278-3285 - 2010
Daniel W. Sherbenou1, Oliver Hantschel2, Ines Kaupe2, Stephanie Willis3, Thomas Bumm3, Lalita P. Turaga3, Thoralf Lange4, Kim-Hien Dao3, Richard D. Press5, Brian J. Druker1,3,6, Giulio Superti-Furga2, Michael W. Deininger3,4
1Cell and Developmental Biology, Oregon Health & Science University, Portland;
2Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
3Division of Hematology & Oncology, Oregon Health & Science University Cancer Institute, Portland;
4Department of Hematology/Oncology, University of Leipzig, Leipzig, Germany;
5Department of Pathology, Oregon Health & Science University, Portland; and
6Howard Hughes Medical Institute, Chevy Chase, MD

Tóm tắt

Abstract Point mutations in the kinase domain of BCR-ABL are the most common mechanism of drug resistance in chronic myeloid leukemia (CML) patients treated with ABL kinase inhibitors, including imatinib. It has also been shown in vitro that mutations outside the kinase domain in the neighboring linker, SH2, SH3, and Cap domains can confer imatinib resistance. In the context of ABL, these domains have an autoinhibitory effect on kinase activity, and mutations in this region can activate the enzyme. To determine the frequency and relevance to resistance of regulatory domain mutations in CML patients on imatinib, we screened for such mutations in a cohort of consecutive CML patients with various levels of response. Regulatory domain mutations were detected in 7 of 98 patients, whereas kinase domain mutations were detected in 29. One mutation (T212R) conferred in vitro tyrosine kinase inhibitor resistance and was associated with relapse, whereas most other mutations did not affect drug sensitivity. Mechanistic studies showed that T212R increased the activity of ABL and BCR-ABL and that T212R-induced resistance may be partially the result of stabilization of an active kinase conformation. Regulatory domain mutations are uncommon but may explain resistance in some patients without mutations in the kinase domain.

Tài liệu tham khảo

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Blood

Tập 116

3278-3285

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