Flt3

The FLT3 gene encodes a class III RTK, which plays an important role in cell proliferation, differentiation, and survival. The FLT3 receptor is preferably expressed on hematopoietic stem cells, and activation by its ligand (FLT3 ligand) induces oligomerization leading to phos-phorylation and activation of downstream pathways (mainly via phosphorylation of intracellular substrates). Mutations of the FLT3 gene are found in up to 40% of AML patients. These mutations include FLT3 ITD, affecting exons 14 and 15, in up to 30% of patients, and activating point mutations of D835 within the activation loop in the tyrosine kinase domain (TKD; Asp835 mutation), in about 5-10% of AML cases. The FLT3 ITD, as well as mutations in the TKD, promote autophos-phorylation of FLT3, and the constitutively active receptor confers ligand-independent proliferation.52

Clinical studies have demonstrated that both adults and children with AML and FLT3 ITD have a significantly inferior clinical outcome.53-60 In some analyses, the worst outcome has been bestowed by FLT3 ITD coupled with lack of an FLT3 wild-type allele or a high FLT3 mutant/wild-type allele ratio.5960 In one study, relatively infrequent patients with simultaneous presence of both the FLT3 ITD and the Asp835 mutation had the least favorable outcome.61 However, although FLT3 ITD is also common in APL patients with t(15;17), it has thus far not been shown to predict prognosis in these patients.555762 Likewise, FLT3 Asp835 mutations have not hitherto been correlated with inferior prognosis, but because they are relatively infrequent, larger clinical studies are necessary to determine their prognostic importance.

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