Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplication (ITD) and D835V mutation (FLT3-ITD D835V)

Fms-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays a pivotal role in the proliferation, survival, and differentiation of hematopoietic progenitor cells (UniProt: P36888). The FLT3-ITD D835V variant is a specific oncogenic form found in acute myeloid leukemia (AML), combining an internal tandem duplication (ITD) in the juxtamembrane domain with a point mutation (D835V) in the kinase activation loop (Levis, 2017). While the ITD mutation causes constitutive, ligand-independent signaling, the D835V mutation frequently emerges as a secondary resistance mechanism during treatment with Type II FLT3 inhibitors like quizartinib (Smith et al., 2012). This dual mutation stabilizes the kinase in its active DFG-in conformation, rendering many conventional inhibitors ineffective. Consequently, therapeutic management requires Type I inhibitors, such as gilteritinib, which can bind to the active state of the enzyme to block downstream oncogenic signaling (Perl et al., 2019). Targeting this specific mutant profile is essential for addressing refractory or relapsed AML and improving patient prognosis.

Other names

CD135FLK-2STK-1Fms-related tyrosine kinase 3Receptor-type tyrosine-protein kinase FLT3

Type I tyrosine kinase inhibition; competitive binding to the ATP-binding pocket of the FLT3 receptor in its active conformation (Perl et al., 2019).