Mutations of two class III receptor tyrosine kinases in acute myelogenous leukemia (AML).FLT3 is mutated in approximately 30% of patients with AML and KIT in 5%. The most common type of mutation consists of internal tandem duplications of amino acids in the juxtamembrane domain. These are variable in length from patient to patient, but are always in frame. These repeat sequences may serve to disrupt auto-inhibitory activity of the juxtamembrane 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. Mutations at a specific aspartic acid residue, D835, which is highly conserved among tyrosine kinases, results in constitutive FLT3 activation. KIT mutations in AML are typically found in the analogous asparagine, D816. Activating loops are thought also to exert auto-inhibitory function by limited access of adenosine triphosphate (ATP) and substrate to the catalytic domain. Mutations at this asparagine are thought to alter the configuration of the activation loop in a manner similar to that of ligand induced conformational changes. KIT mutations in gastrointestinal stromal cell tumors are found in the juxtamembrane (JM) domain or the extracellular domain.