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An amino-acid switch in the BCR-ABL kinase domain modifies sensitivity to imatinib mesylate

Leukemia volume 19, pages 1671–1673 (2005)Cite this article

TO THE EDITOR

Chronic myelogenous leukemia (CML), a clonal hematopoietic stem cell disorder, is characterized by the presence of the BCR-ABL tyrosine kinase (TK) oncogene, the product of Philadelphia (Ph) chromosome that results from a t(9;22)(q34; q11) reciprocal translocation. Imatinib mesylate (Glivec, STI571) inhibits BCR-ABL TK activity and induces specifically leukemic cell apoptosis. This drug has proved very successful for the treatment of CML when administered in the chronic phase. In contrast, in the advanced phase, remissions are less frequent and are followed by the emergence of resistance to imatinib. BCR-ABL gene amplification and mutations in the BCR-ABL kinase domain are the most frequent mechanisms of resistance.1 Mutations causing amino-acid substitution can be classified into four groups: (i) in the imatinib binding site-like T315I mutation, (ii) in the P-loop (ATP phosphate binding loop for ATP) like G250E mutation, (iii) in the activation loop, and (iv) in the C-terminal lobe of the enzyme.1, 2, 3 In the current study, we investigated a new mutation in the P-loop domain G250A detected in a resistant patient. An in vitro functional study was performed using G250A mutant compared to a G250E mutant already characterized and to one of the most resistant mutant T315I engineered in Baf/BCR-ABL cells.

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Acknowledgements

This work was supported by ‘Ligue contre le cancer’ and ‘Association pour la Recherche contre le Cancer’.

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Authors and Affiliations

  1. Laboratoire hématopoïèse leucémique et cible thérapeutique INSERM E0217, Université Victor Segalen Bordeaux II, France

    T Leguay, V Desplat, V Lagarde, G Marit, J Reiffers & F-X Mahon

  2. Service des Maladies du Sang, Hôpital du Haut-Lévèque, Pessac, France

    T Leguay, G Marit, J Reiffers & F-X Mahon

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  1. T Leguay
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  2. V Desplat
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  3. V Lagarde
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Correspondence to F-X Mahon.

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Leguay, T., Desplat, V., Lagarde, V. et al. An amino-acid switch in the BCR-ABL kinase domain modifies sensitivity to imatinib mesylate. Leukemia 19, 1671–1673 (2005). https://doi.org/10.1038/sj.leu.2403831

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