Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

We have recently identified an internal tandem duplication of the human Flt 3 gene in approximately 20% of acute myeloid leukemia (ARIL) cases. In the present study, the,wild-type and the mutant Flt3 genes were transfected int o two IL-3-dependent cell lines, 32D and BA/F3 cells. Mutant Flt3-transfect ed cells exhibited autonomous growth while wild-type Flt3-transfected cells with the continuous stimulation of Flt3 ligand exhibited a minimal prolife ration. Cells expressing mutant Flt3 showed constitutive activation of STAT 5 and MAP kinase, In contrast, Flt3 ligand stimulation caused rapid activat ion of MAP kinase but not STAT5 in cells expressing wild-type Flt3, Finally , we found constitutive activation of MAP kinase and STAT5 in all clinical samples of AML patients with mutant Flt3, Our study shows the significance of internal tandem duplication of Flt3 receptors for leukemia cell expansio n.