Fms-related tyrosine kinase 3 (FLT3) D835 mutation (FLT3-D835)

Fms-related tyrosine kinase 3 (FLT3) with a D835 mutation is a clinically significant mutant form of a Class III receptor tyrosine kinase, primarily associated with acute myeloid leukemia (AML) (Source: UniProt, P36888). The D835 mutation occurs in the activation loop (A-loop) of the kinase domain, where aspartic acid is substituted (most commonly by tyrosine), leading to constitutive, ligand-independent kinase activity (Source: PubMed, PMID: 11238598). This mutation accounts for approximately 7-10% of AML cases and is often referred to as a Tyrosine Kinase Domain (TKD) mutation (Source: PubMed, PMID: 24061611). Unlike the more common FLT3-ITD mutation, D835 mutations often confer resistance to Type II tyrosine kinase inhibitors like quizartinib because they stabilize the active conformation of the kinase (Source: PubMed, PMID: 23300331). Consequently, Type I inhibitors such as gilteritinib and crenolanib are utilized to target this specific mutation, as they can bind to the kinase in its active state (Source: FDA, Xospata Label). Effective management of FLT3-D835 positive AML remains a challenge due to the rapid emergence of secondary resistance mutations and the aggressive nature of the disease.

Other names

FLT3-TKDCD135Fms-related tyrosine kinase 3FLK2STK1

Competitive inhibition of the ATP-binding site within the kinase domain, preventing autophosphorylation and subsequent activation of downstream oncogenic pathways (Source: PubMed, PMID: 29074728).