title: The two major imatinib resistance mutations E255K and T315I enhance the activity of BCR/ABL fusion kinase.
abstract: The resistance to the tyrosine kinase inhibitor imatinib in BCR/ABL-positive leukemias is mostly associated with mutations in the kinase domain of BCR/ABL, which include the most prevalent mutations E255K and T315I. Intriguingly, these mutations have also been identified in some patients before imatinib treatment. Here we examined the effects of these mutations on the kinase activity of a BCR/ABL kinase domain construct that also contained the SH3 and SH2 domains. When expressed in COS7 cells, the BCR/ABL construct with either E255K or T315I exhibited not only the resistance to imatinib but also the increase in activity to induce autophosphorylation as well as tyrosine phosphorylation of various cellular proteins, which included STAT5. The mutant kinases also showed increased activities in in vitro kinase assays. These results raise a possibility that the major imatinib resistance mutations E255K and T315I may confer the growth advantage on leukemic cells to expand in the absence of selective pressure from imatinib treatment.
authors.affiliation: Department of Hematology and Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kurosu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kakihana
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mizuchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001549:Benzamides; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D008894:Milk Proteins; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D013912:Threonine / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008894:Milk Proteins; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D013912:Threonine; D018698:Glutamic Acid; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl