Menin maintains enhancer-promoter interactions in a leukemia-specific manner

Inhibition of the protein-protein interaction between the Mixed Lineage Leukemia (MLL/KMT2A) protein and the adapter protein Menin is a promising therapy for both high-risk MLL-rearranged and NPM1-mutant (NPM1c) acute leukemias. However, the exact function of Menin in transcription regulation remains unclear, limiting our understanding of the utility of Menin inhibitors. Here, we compared the transcriptional responses of MLL-AF4 and NPM1c leukemias to Menin inhibition. We observed broad, acute transcriptional dysregulation in MLL-AF4 cells, whereas NPM1c showed few targets directly regulated by Menin binding. Screening for Menin interacting proteins by co-immunoprecipitation followed by mass spectrometry revealed a greater enrichment for transcriptional regulators and elongation factors in MLL-AF4 cells compared to NPM1c cells, pointing to protein complex and cell context-specific activity. Finally, we used high-resolution Micro-Capture-C to demonstrate that Menin regulates intragenic enhancer activity and maintains enhancer-promoter contacts in MLL-AF4 cells but not in NPM1c cells. Together, our findings show that Menin exerts distinct transcriptional effects depending on the protein complex it associates with, which is key to understanding how patients respond transcriptionally to Menin inhibition in distinct disease contexts.