Molecular characterization and prognostic significance of FLT3 in CML progression.

To characterize the molecular mechanisms involved in the transition from the chronic phase to blast crisis in chronic myelogenous leukemia (CML), gene expression profiles of leukemic cells from patients in the chronic and blast crisis phases were analyzed using an 8.7K cDNA chip and real-time PCR. A transient transfection analysis was conducted to evaluate the role of FLT3, which was significantly upregulated in the blast crisis patients. Abl and c-Kit induction was detected in K562 cells transfected with FLT3 cDNA (K562/FLT3), and Abl and c-Kit levels were reduced in K562/FLT3 cells transfected with FLT3-siRNA (K562/FLT3-siRNA). The induction of FLT3 in CML cells attenuated imatinib-induced apoptosis. The opposite effect was observed in K562/FLT3-siRNA cells. An increased level of cleaved PARP and decreased level of pro-caspase 3 were noted when K562/FLT3-siRNA cells were treated with imatinib. These findings indicate that FLT3 is associated with disease progression, despite imatinib therapy. These results may help in the prediction of disease progression in CML patients and the development of more appropriate therapeutic modalities.