Summary
This project aims to define the mechanisms of action of Menin inhibition in Acute Myeloid Leukemia (AML), particularly KMT2A-rearranged and NPM1 mutant AML, by investigating chromatin structure, protein complex composition, and the impact of combination therapies.
What they want
The project will investigate how KMT2A and Menin containing complexes establish distinct chromatin conformations that drive oncogenic transcriptional programs in AML. It will explore whether blocking the Menin-KMT2A interaction, in combination with inhibitors of other complex members (DOT1L or KAT6A) or Menin degradation via PROTACs, can improve efficacy. Specific aims include: 1) Interrogating chromatin structure and protein complex composition induced by KMT2A and Menin dependent complexes using advanced sequencing and mass spectrometry. 2) Testing the hypothesis that the ubiquitin ligase UBR5 is critically involved in the stability of Menin- and KMT2A-containing chromatin complexes and its impact on chromatin occupancy, conformation, and transcriptional output. 3) Testing the hypothesis that combinations of drugs targeting multiple epigenetic enzymes or Menin directed PROTACs enhance the efficacy of targeting AML-defining chromatin complexes.
Technical requirements
- Genetically engineered cell line models
- Advanced sequencing-based methods
- Mass spectrometry-based proteomics approaches
- Use of proteolysis targeting chimeras (PROTACs)
