Fms-related tyrosine kinase 3 (FLT3) (FLT3)

Fms-related tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase primarily expressed on hematopoietic progenitor cells, where it regulates cell survival, proliferation, and differentiation through pathways like PI3K/AKT and MAPK/ERK (UniProt P36888). In approximately 30% of acute myeloid leukemia (AML) cases, FLT3 undergoes activating mutations, most commonly internal tandem duplications (ITD) in the juxtamembrane domain or point mutations in the tyrosine kinase domain (TKD), such as D835Y (PMID: 32803351). These mutations result in constitutive, ligand-independent kinase activity and are associated with poor clinical outcomes, high blast counts, and increased relapse rates (NIH/NCI). Therapeutic intervention involves small-molecule tyrosine kinase inhibitors (TKIs) like midostaurin, gilteritinib, and quizartinib, which bind to the ATP-binding pocket to inhibit signaling (StatPearls). However, the D835Y mutation specifically alters the activation loop, often conferring resistance to Type II inhibitors like quizartinib while remaining sensitive to Type I inhibitors like gilteritinib (PMID: 29158371). Consequently, FLT3 mutation status is a critical biomarker for patient stratification and the selection of targeted therapies in myeloid malignancies.

Other names

CD135FLK-2STK-1Fms-like tyrosine kinase 3FLK2STK1Stem cell tyrosine kinase 1

Competitive inhibition of the ATP-binding site within the intracellular tyrosine kinase domain, which prevents autophosphorylation and blocks the activation of downstream oncogenic signaling pathways such as PI3K/AKT, MAPK/ERK, and STAT5 (StatPearls; PMID: 32803351).