Purpose/Principle

FLT3, the fms-related tyrosine-kinase 3 receptor, is a membrane protein that is expressed on early hematopoietic progenitor cells which plays an essential role in stem cell survival and myeloid cell differentiation. FLT3 mutations are the most common genetic alterations in acute myeloid leukemia (AML) having been found in 20 to 40% of cases, including acute promyelocytic leukemia (APL), and some cases of hyperdiploid and relapsed MLL-related acute lymphocytic leukemia (ALL). The majority of FLT3 mutations occur as an internal tandem duplication (ITD) of the juxtamembrane portion of the gene (exons 11 and 12). The second most common FLT3 mutation is a missense mutation in exon 20 at aspartic acid residue 835 (D835) in the activation loop of the FLT3 protein. Both alterations constitutively activate the FLT3 protein. AML patients with FLT3 mutations typically have leukocytosis, a normal karyotype and decreased event-free survival. Investigational small molecule inhibitors of FLT3 tyrosine kinase may soon become more widely available for treatment.