Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplication (ITD) and F691L mutation (FLT3-ITD F691L)

FLT3-ITD F691L is a mutated form of the Fms-like tyrosine kinase 3 (FLT3) receptor, a type III receptor tyrosine kinase that plays a pivotal role in the proliferation, survival, and differentiation of hematopoietic progenitor cells [1.1.1, 1.1.3]. The "ITD" refers to an internal tandem duplication in the juxtamembrane domain, which causes constitutive, ligand-independent activation of the receptor and its downstream signaling pathways, such as STAT5, MAPK/ERK, and PI3K/AKT [1.1.2, 1.1.3]. This mutation is found in approximately 25-30% of patients with acute myeloid leukemia (AML) and is associated with a poor prognosis and high relapse rates [1.1.1, 1.1.2]. The "F691L" component is a secondary point mutation, often called the "gatekeeper" mutation, where phenylalanine is replaced by leucine at position 691 in the kinase domain [1.2.1, 1.3.1]. This specific F691L mutation is a major clinical challenge because it confers high-level resistance to many first- and second-generation FLT3 inhibitors, including midostaurin, quizartinib, and gilteritinib [1.2.1, 1.3.2]. The substitution sterically interferes with the binding of these drugs within the ATP-binding pocket of the kinase [1.3.1, 1.4.1]. As a result, FLT3-ITD F691L often emerges during treatment, leading to therapeutic failure and disease progression [1.3.1, 1.3.3]. Current research focuses on developing next-generation inhibitors, such as covalent inhibitors like FF-10101 or multi-kinase inhibitors like tuspetinib, that can effectively target this resistant variant [1.2.5, 1.4.1]. Monitoring for this mutation via next-generation sequencing is essential for guiding salvage therapy in relapsed or refractory AML [1.4.1, 1.4.4].

Other names

FLT3 gatekeeper mutationFLT3-ITD/F691LCD135STK1FLK2Fms-related tyrosine kinase 3Receptor-type tyrosine-protein kinase FLT3

Tyrosine kinase inhibition [1.1.3]