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

C. Miething, S. Feihl, C. Mugler, R. Grundler, N. von Bubnoff, F. Lordick, C. Peschel, Justus Duyster

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish
Pages (from-to)650-657
Number of pages8
Issue number4
StatePublished - Apr 2006
Externally publishedYes


  • Bcr-Abl
  • CML
  • Imatinib
  • Mouse model
  • Resistance


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