title: Dasatinib inhibits proliferation and induces apoptosis in the KASUMI-1 cell line bearing the t(8;21)(q22;q22) and the N822K c-kit mutation.
abstract: Activating mutations of the c-kit gene are frequently found in CBF (core binding factor) leukemias. We evaluated the effect of tyrosine kinase inhibitor dasatinib in leukemic cell lines bearing or not c-kit mutations. Our data demonstrate that in the AML Kasumi-1 cell line, bearing the N822K c-kit mutation, dasatinib is a potent suppressor of c-kit and Src kinase activity and inhibits the phosphorylation of their downstream target AKT, possibly through the Src-mediated VEGF/VEGFR receptor type 2 pathway. Dasatinib also effectively blocks proliferation and induces apoptosis through caspase-3 activation in Kasumi-1 cells. These data further encourage the integration of dasatinib in the treatment of CBF AML with c-kit mutations in the context of clinical trials, which are eagerly anticipated.
authors.affiliation: Second Department of Internal Medicine and Research Institute, Attikon University Hospital, Rimini 1, Haidari, Athens 12462, Greece.
authors.forename: Vassiliki E
authors.initials: VE
authors.lastname: Mpakou
authors.forename: Frieda
authors.initials: F
authors.lastname: Kontsioti
authors.forename: Sotiris
authors.initials: S
authors.lastname: Papageorgiou
authors.forename: Aris
authors.initials: A
authors.lastname: Spathis
authors.forename: Christine
authors.initials: C
authors.lastname: Kottaridi
authors.forename: Kostas
authors.initials: K
authors.lastname: Girkas
authors.forename: Petros
authors.initials: P
authors.lastname: Karakitsos
authors.forename: George
authors.initials: G
authors.lastname: Dimitriadis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dervenoulas
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Pappa
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D000069439:Dasatinib; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014178:Translocation, Genetic; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D000069439:Dasatinib