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

Daniel W. Sherbenou, Oliver Hantschel, Ines Kaupe, Stephanie Willis, Thomas Bumm, Lalita P. Turaga, Thoralf Lange, Kim-Hien Dao, Richard Press, Brian Druker, Giulio Superti-Furga, Michael W. Deininger

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3278-3285
Number of pages8
JournalBlood
Volume116
Issue number17
DOIs
StatePublished - Oct 28 2010

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src Homology Domains
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Mutation
Imatinib Mesylate
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Conformations
Stabilization
Point Mutation
Drug Resistance
Enzymes
Recurrence

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Sherbenou, D. W., Hantschel, O., Kaupe, I., Willis, S., Bumm, T., Turaga, L. P., ... Deininger, M. W. (2010). BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. Blood, 116(17), 3278-3285. https://doi.org/10.1182/blood-2008-10-183665

BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. / Sherbenou, Daniel W.; Hantschel, Oliver; Kaupe, Ines; Willis, Stephanie; Bumm, Thomas; Turaga, Lalita P.; Lange, Thoralf; Dao, Kim-Hien; Press, Richard; Druker, Brian; Superti-Furga, Giulio; Deininger, Michael W.

In: Blood, Vol. 116, No. 17, 28.10.2010, p. 3278-3285.

Research output: Contribution to journalArticle

Sherbenou, DW, Hantschel, O, Kaupe, I, Willis, S, Bumm, T, Turaga, LP, Lange, T, Dao, K-H, Press, R, Druker, B, Superti-Furga, G & Deininger, MW 2010, 'BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib', Blood, vol. 116, no. 17, pp. 3278-3285. https://doi.org/10.1182/blood-2008-10-183665
Sherbenou DW, Hantschel O, Kaupe I, Willis S, Bumm T, Turaga LP et al. BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. Blood. 2010 Oct 28;116(17):3278-3285. https://doi.org/10.1182/blood-2008-10-183665
Sherbenou, Daniel W. ; Hantschel, Oliver ; Kaupe, Ines ; Willis, Stephanie ; Bumm, Thomas ; Turaga, Lalita P. ; Lange, Thoralf ; Dao, Kim-Hien ; Press, Richard ; Druker, Brian ; Superti-Furga, Giulio ; Deininger, Michael W. / BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. In: Blood. 2010 ; Vol. 116, No. 17. pp. 3278-3285.
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