Blood, 15 April 2001, Vol. 97, No. 8, pp. 2193-2193
Point mutations in the FLT3 gene in AML
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 of
FLT3 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 FLT3
is 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 FLT3
mutations 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, unlike
FLT3-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 that
FLT3 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 against
FLT3 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.
James D. Griffin
Dana-Farber Cancer Institute
