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

Sharlandjieva, V.; Chahrour, C.; Lassen, F. H.; Hamley, J. C.; Damianou, A.; Denny, N.; Smith, A. L.; Hester, S. S.; Vendrell, I.; Stam, R. W.; Konopleva, M.; Roy, A.; Davies, J. O. J.; Crump, N. T.; Kessler, B. M.; Milne, T. A.

doi:10.64898/2026.01.16.698179

bioRxiv · 10.64898/2026.01.16.698179

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

Sharlandjieva, V.·Chahrour, C.·Lassen, F. H.·Hamley, J. C.·Damianou, A.·Denny, N.·Smith, A. L.·Hester, S. S.·Vendrell, I.·Stam, R. W.·Konopleva, M.·Roy, A.·Davies, J. O. J.·Crump, N. T.·Kessler, B. M.·Milne, T. A.

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Abstract

Inhibition of the protein-protein interaction between Mixed Lineage Leukemia (MLL) and Menin is a promising therapy for both high-risk MLL-rearranged and NPM1-mutant (NPM1c) acute leukemias, yet the mechanistic basis of this dependency in distinct contexts remains unclear. By comparing the transcriptional responses of MLL::AF4 and NPM1c leukemia models to Menin inhibition, we find broad, acute transcriptional dysregulation in MLL::AF4 cells, but minor transcriptional consequences in NPM1c cells, despite similarities in Menin promoter occupancy. Using high-resolution Micro Capture-C, we discover that Menin drives enhancer activity and maintains enhancer-promoter contacts in MLL::AF4 cells but not in NPM1c cells. Crucially, Menin is also essential for patient-specific enhancer function in primary MLL-rearranged leukemia samples. Proteomic analysis further demonstrates that Menin associates with distinct transcriptional and elongation complexes in MLL::AF4 compared to NPM1c cells, supporting a context-dependent mechanism of action. Together, these findings establish that Menin is not a uniform transcriptional cofactor, but a context-dependent regulator of enhancer connectivity, and identifies enhancer-promoter architecture as a selective vulnerability in MLL-rearranged leukemia.

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Sharlandjieva, V., Chahrour, C., Lassen, F. H., Hamley, J. C., Damianou, A., Denny, N., Smith, A. L., Hester, S. S., Vendrell, I., Stam, R. W., Konopleva, M., Roy, A., Davies, J. O. J., Crump, N. T., Kessler, B. M., Milne, T. A.. 2026-01-17. Menin maintains enhancer-promoter interactions in a leukemia-specific manner. https://doi.org/10.64898/2026.01.16.698179

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