The exact frequency of FLT-3 varies with age with mutations being present in approximately 20 percent of cancer patients with cytogenetically normal AML. There are two major types of FLT-3 mutations. The most common is an ITD on exon 14 of the FLT-3 gene, which varies from 3 to >400 base pairs. It is typically in frame and occurs in the juxta-membrane region of the receptor. This ITD disrupts the auto inhibitory function of the juxta-membrane domain and results in ligandindependent activation of the FLT-3 receptor. This leads to a proliferative signal via activation of its downstream effectors, and produces growth factor-independent proliferation in leukemia cell lines and a fatal myeloproliferative syndrome in murine models. Thus, the ITD leads to gain of function mainly by inducing hyper-responsivity of the FLT-3 receptor to FL rather than through auto-activation of the receptor. Alternatively, point mutations in the activating loop of the kinase domain of FLT-3 may result in tyrosine kinase activation of FLT-3 in 5 to 10 percent of cancer patients. The most common of these activating mutations is the aspartate 835 (D835) mutation, which occurs in approximately 7% of patients with AML.
Pawar R, Bali O P S, Malhotra B K, et al. Recent advances and novel agents for FLT3 mutated AML[J]. Stem Cell Investigation, 2014, 1(3).