Fms-like tyrosine kinase 3 with internal tandem duplication (FLT3-ITD) (FLT3-ITD)

Fms-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays a critical role in the proliferation and differentiation of hematopoietic progenitor cells [UniProt P36888]. The internal tandem duplication (ITD) is a specific mutation occurring in the juxtamembrane domain of the FLT3 receptor, which leads to constitutive, ligand-independent activation of the kinase [PubMed PMID: 30333117]. This aberrant signaling activates multiple downstream pathways, including PI3K/Akt, MAPK/ERK, and STAT5, promoting leukemic cell survival and rapid proliferation [NCI Drug Dictionary]. FLT3-ITD mutations are found in approximately 25-30% of patients with acute myeloid leukemia (AML) and are clinically associated with a high leukemic burden, increased risk of relapse, and poor overall prognosis [PubMed PMID: 29077157]. Therapeutic intervention involves the use of FLT3 inhibitors, such as midostaurin, gilteritinib, and quizartinib, which target the ATP-binding pocket of the receptor to block its activity [FDA Label: Xospata, Vanflyta]. Despite the efficacy of these inhibitors, clinical challenges persist due to the development of secondary resistance mutations in the kinase domain and the transient nature of responses in some patient populations.

Other names

CD135FLK2STK1Fms-related tyrosine kinase 3Fetal liver kinase 2Stem cell tyrosine kinase 1

Small molecule inhibition of the FLT3 kinase domain by competitive binding to the ATP-binding site, thereby preventing autophosphorylation and downstream signaling cascades.