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

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,...

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Bibliographic Details
Published in:Blood 2010-10, Vol.116 (17), p.3278-3285
Main Authors: Sherbenou, Daniel W., Hantschel, Oliver, Kaupe, Ines, Willis, Stephanie, Bumm, Thomas, Turaga, Lalita P., Lange, Thoralf, Dao, Kim-Hien, Press, Richard D., Druker, Brian J., Superti-Furga, Giulio, Deininger, Michael W.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Benzamides
Biological and medical sciences
Cell Line
Chromosome aberrations
Cohort Studies
Drug Resistance, Neoplasm
Female
Fusion Proteins, bcr-abl - chemistry
Fusion Proteins, bcr-abl - genetics
Hematologic and hematopoietic diseases
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical genetics
Medical sciences
Middle Aged
Models, Molecular
Mutation
Myeloid Neoplasia
Piperazines - therapeutic use
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Protein Kinases - metabolism
Pyrimidines - therapeutic use
src Homology Domains
Young Adult
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-10-183665