Two types of activating mutations in FLT3 are associated with AML.

The first type consists of ITDs of amino acids in the JM domain. These are variable in length from patient to patient, but are always in-frame. These repeat sequences may serve to disrupt autoinhibitory activity of the JM domain resulting in constitutive tyrosine kinase activation. The second type of mutation are point mutations in the so-called activation loop of the second tyrosine kinase domain. Mutation at a specific aspartic acid residue, Asp835, which is highly conserved among tyrosine kinases, also results in constitutive FLT3 activation. In the context of other tyrosine kinases, activation loops are thought also to exert autoinhibitory function by limited access of ATP and substrate to the catalytic domain. Mutations at this site are thought to alter the configuration of the activation loop in a manner similar to that of ligand-induced conformational changes, resulting in increased access of ATP and substrate. ECD indicates extracellular domain; TM, transmembrane domain; JM, juxtamembrane domain; TK, tyrosine kinase domain; KI, kinase insert.