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

Fms-related tyrosine kinase 3 (FLT3) with internal tandem duplication (ITD) is a constitutively active mutant form of a Class III receptor tyrosine kinase that plays a critical role in the pathogenesis of acute myeloid leukemia (AML) (MDPI, 2024; MedlinePlus, 2022). The ITD mutation occurs in the juxtamembrane domain of the receptor, disrupting its auto-inhibitory function and leading to ligand-independent dimerization and activation (MedlinePlus, 2022; NIH, 2022). This results in the persistent stimulation of downstream signaling cascades, including the PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and JAK/STAT5 pathways, which drive the uncontrolled proliferation and survival of hematopoietic progenitor cells (MDPI, 2024; NIH, 2017). FLT3-ITD is one of the most common genetic alterations in AML, present in approximately 20-25% of cases, and is clinically associated with a high leukemic burden, increased risk of relapse, and poor overall survival (NIH, 2022; NIH, 2017). Therapeutic management involves the use of FLT3 inhibitors, such as midostaurin, gilteritinib, and quizartinib, which aim to block the kinase activity of the mutant receptor (AML Hub, 2026; MDPI, 2024). These inhibitors are categorized into Type I, which bind the active conformation, and Type II, which bind the inactive conformation of the receptor (AML Hub, 2026). However, the efficacy of these agents is often limited by the emergence of secondary resistance mutations in the tyrosine kinase domain, such as the F691L gatekeeper mutation, necessitating the development of next-generation inhibitors and combination treatment strategies (NIH, 2022; ResearchGate, 2012). Monitoring the FLT3-ITD allelic ratio and measurable residual disease is essential for risk stratification and evaluating treatment response in clinical practice (NIH, 2022; AML Hub, 2026).

Other names

CD135Fetal liver kinase 2FLK2STK1Stem cell kinase 1Fms-like tyrosine kinase 3FLT3-ITD mutant

Tyrosine kinase inhibition