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

Fms-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase primarily expressed on hematopoietic stem and progenitor cells, where it plays a critical role in regulating survival, proliferation, and differentiation [4, 10, 11]. The internal tandem duplication (ITD) mutation is a gain-of-function alteration characterized by the duplication of genetic sequences within the juxtamembrane domain, which disrupts the receptor's auto-inhibitory function [5, 12, 14]. This structural change results in ligand-independent dimerization and constitutive activation of signaling cascades such as PI3K/AKT, MAPK/ERK, and STAT5, promoting uncontrolled leukemic cell growth and survival [1, 11, 14]. Clinically, FLT3-ITD is one of the most common mutations in Acute Myeloid Leukemia (AML), appearing in approximately 25-30% of adult cases and conferring a poor prognosis characterized by high leukemic burden and increased relapse risk [5, 8, 11]. Targeted therapies using small-molecule tyrosine kinase inhibitors (TKIs) like midostaurin and gilteritinib have become standard treatments, though clinical utility is often limited by the emergence of secondary resistance mutations and protective signals from the bone marrow microenvironment [2, 11, 20].

Other names

FLT3-ITDCD135STK1FLK2FMS-related tyrosine kinase 3

Small-molecule competitive inhibition of the adenosine triphosphate (ATP) binding site in the tyrosine kinase domain, preventing receptor autophosphorylation and subsequent constitutive activation of downstream oncogenic signaling pathways including PI3K/AKT, MAPK/ERK, and STAT5 [1, 11, 14, 20].