Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy

A. Hochhaus, S. Kreil, A. S. Corbin, P. La Rosée, M. C. Müller, T. Lahaye, B. Hanfstein, C. Schoch, N. C P Cross, U. Berger, H. Gschaidmeier, Brian Druker, R. Hehlmann

Research output: Contribution to journalArticle

735 Citations (Scopus)

Abstract

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (ST1571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n=33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.

Original languageEnglish (US)
Pages (from-to)2190-2196
Number of pages7
JournalLeukemia
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2002

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Protein-Tyrosine Kinases
Clonal Evolution
Blast Crisis
Therapeutics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Imatinib Mesylate
Oncogene Proteins
Fluorescence In Situ Hybridization
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Point Mutation
Cytogenetics
Chromosome Aberrations
Binding Sites
Mutation

Keywords

  • BCR-ABL
  • Chronic myelogenous leukemia
  • Imatinib
  • Resistance
  • STI571

ASJC Scopus subject areas

  • Cancer Research

Cite this

Hochhaus, A., Kreil, S., Corbin, A. S., La Rosée, P., Müller, M. C., Lahaye, T., ... Hehlmann, R. (2002). Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia, 16(11), 2190-2196. https://doi.org/10.1038/sj.leu.2402741

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. / Hochhaus, A.; Kreil, S.; Corbin, A. S.; La Rosée, P.; Müller, M. C.; Lahaye, T.; Hanfstein, B.; Schoch, C.; Cross, N. C P; Berger, U.; Gschaidmeier, H.; Druker, Brian; Hehlmann, R.

In: Leukemia, Vol. 16, No. 11, 01.11.2002, p. 2190-2196.

Research output: Contribution to journalArticle

Hochhaus, A, Kreil, S, Corbin, AS, La Rosée, P, Müller, MC, Lahaye, T, Hanfstein, B, Schoch, C, Cross, NCP, Berger, U, Gschaidmeier, H, Druker, B & Hehlmann, R 2002, 'Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy', Leukemia, vol. 16, no. 11, pp. 2190-2196. https://doi.org/10.1038/sj.leu.2402741
Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002 Nov 1;16(11):2190-2196. https://doi.org/10.1038/sj.leu.2402741
Hochhaus, A. ; Kreil, S. ; Corbin, A. S. ; La Rosée, P. ; Müller, M. C. ; Lahaye, T. ; Hanfstein, B. ; Schoch, C. ; Cross, N. C P ; Berger, U. ; Gschaidmeier, H. ; Druker, Brian ; Hehlmann, R. / Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. In: Leukemia. 2002 ; Vol. 16, No. 11. pp. 2190-2196.
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