title: Internal tandem duplication and tyrosine kinase domain mutations inFLT3alter the response to daunorubicin in Ba/F3 cells.
abstract: Internal tandem duplication (ITD) and activating point mutations, mainly at aspartic acid 835 in the tyrosine kinase domain (TKD), are frequently identified in the Fms-related tyrosine kinase 3 (FLT3) receptor gene in acute myeloid leukemia. The ITD inFLT3(FLT3-ITD) confers resistance to several chemotherapeutic drugs; however, the relative effects ofFLT3-ITD andFLT3-TKD mutations on the efficacy of these drugs have not been reported. In the present study, ITD or TKD mutant forms ofFLT3in Ba/F3 cells were expressed, as in the absence of interleukin-3 (IL-3) the growth of these cells is completely dependent onFLT3oncogenic signals. As a result, the 50% effective dose for daunorubicin was significantly higher in both Ba/F3-FLT3-ITD clones, and also in one of the two Ba/F3-FLT3-TKD clones when cells were cultured without IL-3. This phenomenon was not observed for cytarabine in either Ba/F3-FLT3-ITD or Ba/F3-FLT3-TKD cells. Collectively, these results indicate that ITD and TKD mutations inFLT3may confer daunorubicin resistance in Ba/F3 cells.
authors: Division of Hematology, Kitasato University School of Allied Health Sciences, Kanagawa 252-0373, Japan.
authors: Shinichiro
authors: S
authors: Takahashi
authors: Division of Hematology, Kitasato University School of Allied Health Sciences, Kanagawa 252-0373, Japan.
authors: Kumi
authors: K
authors: Shirahama
keywords: Ba/F3 cells; FLT3-internal tandem duplication; FLT3-tyrosine kinase domain; daunorubicin; drug resistance