Fms-related receptor tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutant (FLT3-ITD)

Fms-related receptor tyrosine kinase 3 (FLT3) with internal tandem duplication (ITD) is a constitutively active mutant receptor that plays a critical role in the pathogenesis of acute myeloid leukemia (AML) [1.2.1, 1.3.3]. The ITD mutation, occurring in the juxtamembrane domain, leads to ligand-independent dimerization and activation of the kinase, triggering downstream signaling through the STAT5, PI3K/AKT, and MAPK/ERK pathways [1.2.2, 1.3.2]. This aberrant signaling promotes rapid cell proliferation, survival, and a block in myeloid differentiation, resulting in an aggressive disease phenotype with a high risk of relapse and poor overall survival [1.3.3, 1.3.4]. FLT3-ITD is a major therapeutic target, with several tyrosine kinase inhibitors (TKIs) approved for clinical use, including midostaurin, gilteritinib, and quizartinib [1.1.1, 1.2.1]. These drugs are often categorized as Type I inhibitors, which target both ITD and tyrosine kinase domain (TKD) mutations, or Type II inhibitors, which are more selective for the ITD variant [1.3.2, 1.3.3]. Despite the success of these targeted therapies, clinical challenges persist due to the development of secondary resistance mutations, such as the F691L gatekeeper mutation, and off-target toxicities like myelosuppression and QTc prolongation [1.2.2, 1.3.5].

Other names

CD135FLK2STK1Fms-related receptor tyrosine kinase 3 mutantFLT3-ITD+Fms-like tyrosine kinase 3 internal tandem duplication

Tyrosine kinase inhibition, ATP-competitive inhibition, inhibition of autophosphorylation