Drug-resistant menin variants retain high binding affinity and interactions with MLL1

Area of Science:

• Oncology
• Structural Biology
• Biochemistry

Background:

• Menin is a crucial cofactor for MLL1 fusion proteins in acute leukemias.
• Menin-MLL1 interaction inhibitors are in clinical trials for leukemia treatment.
• Somatic mutations in menin are emerging as a cause of resistance to these inhibitors.

Purpose of the Study:

• To investigate how patient-derived menin mutations impact MLL1 binding.
• To structurally characterize menin mutants and their complexes with MLL1.
• To understand the mechanisms of resistance to menin-targeted therapies.

Main Methods:

• Systematic characterization of binding affinity for menin mutants (T349M, M327I, G331R, G331D) with MLL1.
• Determination of crystal structures of menin patient mutants complexed with MLL1-derived peptides.

Main Results:

• Menin mutations conferring drug resistance are adjacent to the MLL1 binding site and do not impair MLL1 binding.
• These mutations induce steric clashes with menin inhibitors.
• The G331D mutation significantly slows MLL1 dissociation from menin, complicating small molecule inhibition.

Conclusions:

• Menin mutations cause resistance by interfering with drug binding, not MLL1 interaction.
• Structural insights guide the development of next-generation menin inhibitors overcoming resistance.
• The G331D mutation highlights a specific challenge for future drug design in leukemia treatment.