Fms-like tyrosine kinase 3 (D835Y mutation) (FLT3/D835Y)

Fms-like tyrosine kinase 3 (FLT3) is a Class III receptor tyrosine kinase primarily expressed on hematopoietic progenitor cells, where it plays a vital role in regulating cell survival, proliferation, and differentiation through pathways such as STAT5, MAPK, and PI3K/AKT [1, 11]. The D835Y mutation is a specific point mutation located within the activation loop (A-loop) of the kinase domain, which leads to constitutive, ligand-independent activation of the receptor [2, 3]. This mutation is found in approximately 5-10% of patients with Acute Myeloid Leukemia (AML) and is a common mechanism of acquired resistance to Type II FLT3 inhibitors like quizartinib and sorafenib [7, 10]. Structurally, the D835Y substitution stabilizes the kinase in an active "DFG-in" conformation, making it sensitive to Type I inhibitors such as gilteritinib and midostaurin, which can bind to the active state [7, 14]. Targeting the FLT3/D835Y mutant is a critical therapeutic strategy for managing both de novo and relapsed/refractory AML, although clinical management is often complicated by the emergence of secondary resistance mutations and treatment-related toxicities like myelosuppression [4, 16].

Other names

CD135FLK2STK1Fms-related tyrosine kinase 3FLT3-TKDFetal liver kinase 2Stem cell tyrosine kinase 1

Tyrosine kinase inhibition