The Bcr-Abl mutations T315I and Y253H do not confer a growth advantage in the absence of imatinib
| Autor: | N von Bubnoff, Justus Duyster, Rebekka Grundler, Cornelius Miething, Claudia Mugler, Christian Peschel, Florian Lordick, S Feihl |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research Mutant Fusion Proteins bcr-abl Antineoplastic Agents Bone Marrow Cells In Vitro Techniques Biology Philadelphia chromosome medicine.disease_cause Piperazines Mice In vivo hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Phosphorylation Kinase activity neoplasms Cell Proliferation Mice Inbred BALB C Mutation Gene Transfer Techniques Imatinib Hematology Protein-Tyrosine Kinases Cell Transformation Viral medicine.disease Molecular biology Enzyme Activation Transplantation Disease Models Animal Pyrimidines Retroviridae Imatinib mesylate Amino Acid Substitution Oncology Benzamides Imatinib Mesylate NIH 3T3 Cells Cancer research Neoplasm Transplantation medicine.drug |
| Zdroj: | Leukemia. 20:650-657 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/sj.leu.2404151 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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