Receptor-type tyrosine-protein kinase FLT3 (FLT3) D835Y mutant (FLT3-D835Y)

Receptor-type tyrosine-protein kinase FLT3 (FLT3) with the D835Y mutation is a constitutively active variant of the FLT3 receptor, a member of the type III receptor tyrosine kinase family [2, 6]. This specific mutation involves a substitution of aspartic acid with tyrosine at position 835 within the activation loop of the kinase domain [6, 10]. This change stabilizes the enzyme in its active 'DFG-in' conformation, resulting in ligand-independent autophosphorylation and continuous activation of downstream signaling pathways, including PI3K/AKT, MAPK/ERK, and STAT5 [7, 8, 12]. These pathways promote the survival, proliferation, and impaired differentiation of hematopoietic progenitor cells, contributing significantly to the pathogenesis of acute myeloid leukemia (AML) [1, 9, 13]. FLT3-D835Y is clinically significant as it often confers resistance to Type II FLT3 inhibitors, such as quizartinib and sorafenib, which require the receptor to be in an inactive state for binding [5, 7, 16]. In contrast, Type I inhibitors like gilteritinib and midostaurin remain effective against this mutant form, making them critical components of targeted therapy for AML patients harboring this genetic alteration [1, 6, 13]. Therapeutic management of this target requires careful monitoring of mutation status and management of common kinase inhibitor toxicities such as myelosuppression and QTc prolongation [11, 12]. The emergence of D835Y as a secondary mutation highlights the dynamic nature of clonal evolution in AML under the pressure of targeted therapy [14, 16].

Other names

CD135FLK2STK1Fms-related tyrosine kinase 3FLT3-TKDFLT3 activation loop mutant

Tyrosine kinase inhibition