Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies

A FLT3 gene frequently undergoes mutations in acute myeloid leukemia
(AML), with internal tandem duplications (ITD) and tyrosine kinase domain
(TKD) point mutations (PMs) being most common. Recently, PMs and deletions
in the FLT3 juxtamembrane domain (JMD) have been identified, but their
biological and clinical significance remains poorly understood. We
analyzed 1660 patients with de novo AML and found FLT3-JMD mutations,
mostly PMs, in 2% of the patients. Patients with FLT3-JMD mutations had a
higher relapse rate and shorter disease-free survival than those with
FLT3-TKD, whereas their relapse rate, disease-free and overall survival
were not significantly different from those of FLT3-ITD-positive patients.
In vitro experiments showed that FLT3-JMD PMs transformed hematopoietic
cells and responded well to type I and II FLT3 inhibitors. Molecular
dynamics simulations were used to explore the conformational changes of
JMD PMs relative to wild-type FLT3. These mutations exhibited constrained
domain motions with wider gate openings, potentially enhancing drug
binding. Altered residue interactions and structural changes shed light on
their unique functional mechanisms, with increased allosteric pathways
suggesting reduced interactions with other residues. We conclude that
patients with FLT3-JMD PMs represent uncommon but important subset with
distinct molecular and biological features, and may benefit from FLT3
inhibitors.