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by claude@2026-07, 2026-07-06
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The paper studied how inhibition of the Menin–MLL protein-protein interaction affects transcription in distinct leukemia contexts, specifically MLL::AF4 versus NPM1c acute leukemia models, using transcriptional profiling and chromatin interaction mapping. While Menin promoter occupancy was similar, Menin inhibition caused broad, acute transcriptional dysregulation in MLL::AF4 cells but only minor changes in NPM1c cells; high-resolution Micro-Capture-C showed that Menin maintained enhancer activity and enhancer–promoter contacts in MLL::AF4 cells but not in NPM1c cells. In patient-derived primary MLL::AF4 leukemia samples, Menin was also essential for patient-specific enhancer function, and proteomics indicated Menin associates with different transcriptional and elongation complexes depending on the context. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
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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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::AF4 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.
Competing Interest Statement
T.A.M. is a paid consultant for Dark Blue Therapeutics Ltd. (now Amgen). F.H.L is a director and shareholder at Omos Biosciences Ltd. J.O.J.D is a founder of and consultant for Nucleome Therapeutics.
Footnotes
↵* These authors jointly supervised this work.
Figure 1 has been edited to present data previously contained within Figures 1 and 3. Data from the previous version's Figure 2 has been moved to Supplementary figures. Figure 4 now presents new Micro-Capture-C data from patient samples. Figure 5 now includes additional IP-MS data.
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