Fms-related receptor tyrosine kinase 3 (FLT3) D835Y mutant (FLT3 D835Y)

Fms-related receptor tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that is essential for the normal development, proliferation, and survival of hematopoietic stem and progenitor cells [4, 6]. The D835Y mutation is a common point mutation located within the highly conserved activation loop of the tyrosine kinase domain (TKD), which results in the constitutive, ligand-independent activation of the receptor [1, 11]. This gain-of-function mutation triggers downstream signaling pathways, including STAT5, MAPK/ERK, and PI3K/Akt, leading to uncontrolled cellular proliferation and resistance to apoptosis [3, 5]. Found in approximately 5-10% of patients with acute myeloid leukemia (AML), the D835Y mutation is also a frequent mechanism of acquired resistance in patients treated with Type II FLT3 inhibitors like quizartinib, which only bind to the inactive conformation of the kinase [2, 12]. In contrast, Type I inhibitors such as gilteritinib and midostaurin are capable of inhibiting the D835Y mutant by binding to the active conformation of the receptor [7, 9]. Effective targeting of this specific mutation is a critical therapeutic strategy for overcoming clinical relapse and improving the prognosis of patients with FLT3-mutated hematologic malignancies [14, 15].

Other names

CD135FLK2STK1Fms-like tyrosine kinase 3 D835YReceptor-type tyrosine-protein kinase FLT3 D835Y mutant

Inhibition of the constitutively active tyrosine kinase signaling by binding to the ATP-binding site of the FLT3 receptor in its active or inactive conformation.