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Chronic Myeloid Leukemia, BCR/ABL Studies and Myeloproliferative Disorders

The Bcr-Abl mutations T315I and Y253H do not confer a growth advantage in the absence of imatinib

Leukemia volume 20, pages 650–657 (2006)Cite this article

Abstract

Mutations in the Bcr-Abl kinase domain are a frequent cause of imatinib resistance in patients with advanced CML or Ph+ ALL. The impact of these mutations on the overall oncogenic potential of Bcr-Abl and on the clinical course of the disease in the absence of imatinib is presently unclear. In this study, we analyzed the effects of the Bcr-Abl P-loop mutation Y253H and the highly imatinib resistant T315I mutation on kinase activity in vitro and transforming efficiency of Bcr-Abl in vitro and in vivo. Immunoprecipitated Bcr-AblY253H and Bcr-AblT315I proteins displayed similar kinase activities and substrate phosphorylation patterns as Bcr-Abl wildtype. We directly compared the proliferative capacity of mutant to wildtype Bcr-Abl in primary BM cells in vitro and in a murine transplantation model of CML by using a competitive repopulation assay. The results implicate that in the absence of imatinib, there is no growth advantage for cells carrying Bcr-AblT315I or Bcr-AblY253H compared to Bcr-Ablwt, whereas imatinib treatment clearly selects for leukemic cells expressing mutant Bcr-Abl both in vitro and in vivo. Thus, the analysed Bcr-Abl mutants confer imatinib resistance, but do not induce a growth advantage in the absence of imatinib.

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Acknowledgements

This work was supported by a grant from the BMBF (NGFN II) to JD. CM was supported by a fellowship from the Deutsche Jose Carreras Leukämie Stiftung (DJCLS2001/NAT-2).

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  1. C Miething and S Feihl: These authors contributed equally.

Authors and Affiliations

  1. Department of Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Trogerstr, Munich, Germany

    C Miething, S Feihl, C Mugler, R Grundler, N von Bubnoff, F Lordick, C Peschel & J Duyster

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  1. C Miething
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  2. S Feihl
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  3. C Mugler
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Correspondence to J Duyster.

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Miething, C., Feihl, S., Mugler, C. et al. The Bcr-Abl mutations T315I and Y253H do not confer a growth advantage in the absence of imatinib. Leukemia 20, 650–657 (2006). https://doi.org/10.1038/sj.leu.2404151

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