Biological Sciences Division
Published January 13, 2025 | Version v1
Journal article Open

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

Creators

  • 1. The Ohio State University
  • 2. Zucker School of Medicine at Hofstra/Northwell
  • 3. Atrium Health Wake Forest Baptist Comprehensive Cancer Center
  • 4. Emory University
  • 5. University of Maryland
  • 6. University of Cincinnati
  • 7. University of Chicago
  • 8. Washington University in St. Louis

Description

The 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.

Data availability

The Single cell nested amplification sanger sequencing (scNASS) dataset generated and analyzed during the current study is available in the DRYAD repository, https://datadryad.org, https://doi.org/10.5061/dryad.xgxd254rf. All other data generated and analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Prognostic-biological-and-structural-implications-of-FLT3-JMD-point-mutations-in-acute-myeloid-leukemia.pdf

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Additional details

Identifiers

DOI
10.1038/s41375-024-02498-y
Other
oai:uchicago.tind.io:14399

Funding

National Cancer Institute
U10CA180821
National Cancer Institute
U10CA180882
National Cancer Institute
U24CA196171
National Cancer Institute
UG1CA233331
National Cancer Institute
UG1CA189850
National Cancer Institute
UG1CA189824
National Cancer Institute
UG1CA233247
National Cancer Institute
UG1CA233327
National Cancer Institute
UG1CA233339
National Cancer Institute
UG1CA233338
Cancer Center
Support Grant
OSUCCC Pelotonia Foundation

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine