Fms-like tyrosine kinase 3 (FLT3) receptor D835H mutant (FLT3-D835H)

Fms-like tyrosine kinase 3 (FLT3) D835H is a specific point mutation located in the activation loop of the FLT3 receptor, a class III receptor tyrosine kinase essential for normal hematopoiesis [1, 2]. This mutation involves the substitution of aspartic acid with histidine at residue 835, which results in the constitutive, ligand-independent activation of the kinase domain [1, 8]. The D835H variant stabilizes the active 'DFG-in' conformation of the protein, leading to the continuous stimulation of downstream signaling pathways such as STAT5, PI3K/AKT, and MAPK/ERK [2, 10]. In the context of oncology, this mutation is a frequent driver in acute myeloid leukemia (AML) and is often associated with poor prognosis and disease relapse [5, 6]. Therapeutically, FLT3-D835H is a critical target because it confers resistance to Type II tyrosine kinase inhibitors, such as quizartinib and sorafenib, which preferentially bind the inactive conformation [3, 4]. Consequently, Type I inhibitors like gilteritinib and midostaurin, which can bind the active state, are utilized to treat patients harboring this mutation [1, 4]. Clinical management of AML increasingly relies on the detection of D835H as a biomarker to tailor inhibitor therapy and monitor for emerging drug resistance [9, 10]. Safety concerns associated with targeting this mutant include myelosuppression and QTc prolongation, which require careful clinical monitoring [11, 12].

Other names

FLT3-TKD mutationCD135STK1FLK2Fms-related tyrosine kinase 3 D835H

Inhibition of the tyrosine kinase activity of the mutant FLT3 receptor, blocking downstream signaling pathways including STAT5, PI3K/AKT, and MAPK/ERK.