Approximately 20% of acute myeloid leukemia (AML) patients have been found to have constitutive activation of the FLT3-receptor tyrosine kinase due to internal tandem duplications of the juxtamembrane domain (FLT3-ITD). Yamamoto and colleagues (page 2434) now report that Asp835 in the kinase domain ofFLT3 is mutated in an additional 7% of AML patients (30 of 429). Asp835 mutations were also found in 1 of 29 myelodysplastic syndrome patients and 1 of 36 acute lymphocytic leukemia patients, while none were detected in a broad range of other hematologic malignancies. Taken together, these results indicate that FLT3is the single most commonly mutated gene in AML. As is the case for FLT3-ITD, Asp835 mutations spontaneously activate tyrosine kinase activity and induce factor-independent proliferation of hematopoietic cell lines. Although the role of FLT3mutations in the transformation of myeloid cells is not yet known, it is highly likely that they provide a strong mitogenic and antiapoptotic signal. Thus these mutations may act synergistically with mutations blocking differentiation to induce AML. Interestingly, unlikeFLT3-ITD mutations, the Asp835 mutations were not associated with higher white blood cell counts or poorer survival.
The Asp835 residue is located in a region predicted to function as an “activation loop.” When the receptor is inactive, this loop folds into the active site of the kinase, blocking access. The loop folds out after receptor activation and phosphorylation of a nearby tyrosine residue. Based on detailed studies of the insulin receptor, mutations in this highly conserved asparagine residue probably cause the activation loop to adopt the active configuration in the absence of ligand. The mechanism of activation of FLT3 by the more common juxtamembrane tandem duplications is probably different, perhaps inducing spontaneous dimerization and/or rotation of the receptors.
This study is important for several reasons. First, it shows thatFLT3 can be activated by mutation of the same asparagine residue already known to activate c-KIT in mastocytosis and gastrointestinal sarcomas. Second, it significantly extends the number of patients with AML that harbor mutations in FLT3.Small-molecule tyrosine kinase inhibitors active againstFLT3 are under development and could prove to have significant clinical activity. Finally, it suggests that we may still be seeing only the tip of the iceberg. A careful search for activation of other tyrosine kinases in other types of hematologic malignancies is warranted.