IntroductionAcute myeloid leukemia (AML) is an aggressive form of a malignant disorder of the hematopoietic system that shows increasing incidence with age and is characterized by highly proliferative blast cells. [1][2][3] Aberrant activity of tyrosine kinases has been shown to be present in various malignant diseases and AML is no exception. The FMS-like tyrosine kinase 3 (FLT3) gene in chromosome band 13q12 encodes a receptor tyrosine kinase that belongs to the same family as FMS, KIT, and the 2 genes encoding PDGFR␣ and . [4][5][6][7] It is normally expressed by hematopoietic stem/progenitor cells (HSPCs) and as hematopoietic cells differentiate FLT3 expression is lost. [8][9][10][11] A large body of work has shown that FLT3 plays roles in survival, proliferation, and differentiation. Aside from its role in regulating normal hematopoiesis, FLT3 is also highly expressed in several hematologic malignancies. 7 Mutations in the receptor, in the form of internal tandem duplication (ITD) of the juxtamembrane domain and point mutations of the kinase domain, both result in constitutive activation. 7 These mutations occur in one third of AML patients making it one of the most commonly mutated genes in AML. 12,13 Patients with FLT3/ITD mutations have been demonstrated to have very poor prognosis. 5,14,15 However, the molecular basis by which FLT3/ITD mutations lead to aggressive disease and poor prognosis in AML is not yet clearly understood.The process of activation, internalization, and degradation of FLT3 occurs in a similar fashion to other members of the class III receptor-type tyrosine kinases (RTKs) family. 16 Binding of FLT3 ligand (FL) causes homodimerization, tyrosine kinase activation, receptor autophosphorylation, and initiation of downstream signaling cascades. 7 The FLT3 receptor kinase shares structural homology with other type III receptor kinases, such as KIT and FMS, with all 3 playing an important role in survival, proliferation, and differentiation of hematopoietic cells. 17 We and other investigators have shown that STAT5 is one of the principal pathways involved in mediating gene expression in response to constitutive receptor activation through mutation. FLT3 signaling results in activation of pathways through phosphorylation of STAT5, MAPK, AKT, VAV, CBL, and BAD. [18][19][20] Phosphorylation and activation of STAT5 by FLT3/ITD mutants are particularly strong compared with its phosphorylation in the wild-type FLT3 allele. 21 STAT5 tyrosine phosphorylation mediates STAT5 protein dimerization through a mechanism involving SH2 domains and N-terminal regions and results in translocation to the nucleus where it activates transcription of a number of genes. 22 However, recent data suggest that STAT5 may have other interacting partners. 23,24 For example, signal-transducing adapter proteins (STAPs) have been shown to constitutively interact with inactive STAT5 in the cytoplasm but dissociate when STAT5 is phosphorylated. 24 STAT5 is also phosphorylated on serine residues, possibly by the ERK1/2 prote...
