Fms-like tyrosine kinase 3 (FLT3)

Fms-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase essential for the proliferation, survival, and differentiation of hematopoietic progenitor cells. FLT3 is normally activated by binding its ligand (FLT3 ligand), which triggers dimerization and autophosphorylation, stimulating several intracellular signaling cascades. Activating mutations of FLT3, notably internal tandem duplications (ITD) and point mutations at aspartic acid 835 (e.g., D835Y), cause constitutive kinase activation independent of ligand and are prevalent in acute myeloid leukemia (approximately one-third of cases). The D835Y mutant specifically refers to a substitution at codon 835 in the activation loop of the kinase domain, converting aspartic acid to tyrosine—this is the most frequent point mutation among FLT3 kinase domain mutations. FLT3 D835Y results in abnormal cellular proliferation and survival that drive myeloid and lymphoid neoplasms, although its associated disease phenotype is, on average, less aggressive than that driven by FLT3-ITD mutations. FLT3 D835Y and other activating mutations are major therapeutic targets in AML, with multiple small-molecule kinase inhibitors developed and approved. Resistance to FLT3 inhibition—especially via additional kinase domain mutations such as D835Y—remains a significant clinical challenge.

Other names

FMS-like tyrosine kinase 3Fms related receptor tyrosine kinase 3FLT3CD135Fetal liver kinase 2FL cytokine receptorFLK2STK1

Inhibition of FLT3 kinase activity (competitive and covalent inhibitors) Blockade of constitutive mutant FLT3 signaling (D835Y and other activating mutations)