ArticleThe Journal of biological chemistry2010
Molecular basis of the mixed lineage leukemia-menin interaction: implications for targeting mixed lineage leukemias.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 93 citations in OpenAlex.
- Menin inhibitors as a treatment for acute leukemia: from bench to the clinic.Blood neoplasia · 2026Review
- Menin Inhibition in Acute Myeloid Leukemia: Rewiring Leukemic Transcriptional Networks.International journal of molecular sciences · 2026Review
- Clinical Integration of Menin Inhibitors in AML: Evolving Data and Therapeutic Perspectives.Oncology research · 2026Review
- Dysregulation of HOXA genes in acute myeloid leukemia and targeted therapy.NPJ precision oncology · 2025Review
- ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program.bioRxiv : the preprint server for biology · 2025Article
- Insights into KMT2A rearrangements in acute myeloid leukemia: from molecular characteristics to targeted therapies.Biomarker research · 2025Review
- Menin: from molecular insights to clinical impact.Epigenomics · 2025Review
- Design of Potent Menin-KMT2A Interaction Inhibitors with ImprovedACS medicinal chemistry letters · 2025Article
- Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions.Cancers · 2024Review
- A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia.Hematology reports · 2024Review
- AAp-MSMD: Amino Acid Preference Mapping on Protein-Protein Interaction Surfaces Using Mixed-Solvent Molecular Dynamics.Journal of chemical information and modeling · 2023Article
- Article
- Review
- Pattern enrichment analysis for phage selection of stapled peptide ligands.Chemical science · 2022Article
- Automated affinity selection for rapid discovery of peptide binders.Chemical science · 2021Article
- Structure, function and inhibition of critical protein-protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins.Journal of hematology & oncology · 2021Review
- Targeting epigenetic protein-protein interactions with small-molecule inhibitors.Future medicinal chemistry · 2020Review
- Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with StrongJournal of medicinal chemistry · 2020Article
- Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia.The Journal of clinical investigation · 2020Article
- Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chromosomal translocations targeting the mixed lineage leukemia (MLL) gene result in MLL fusion proteins that are found in aggressive human acute leukemias. Disruption of MLL by such translocations leads to overexpression of Hox genes, resulting in a blockage of hematopoietic differentiation that ultimately leads to leukemia. Menin, which directly binds MLL, has been identified as an essential oncogenic co-factor required for the leukemogenic activity of MLL fusion proteins. Here, we characterize the molecular basis of the MLL-menin interaction. Using (13)C-detected NMR experiments, we have mapped the residues within the intrinsically unstructured fragment of MLL that are required for binding to menin. Interestingly, we found that MLL interacts with menin with a nanomolar affinity (K(d) ∼ 10 nM) through two motifs, MBM1 and MBM2 (menin binding motifs 1 and 2). These motifs are located within the N-terminal 43-amino acid fragment of MLL, and the MBM1 represents a high affinity binding motif. Using alanine scanning mutagenesis of MBM1, we found that the hydrophobic residues Phe(9), Pro(10), and Pro(13) are most critical for binding. Furthermore, based on exchange-transferred nuclear Overhauser effect measurements, we established that MBM1 binds to menin in an extended conformation. In a series of competition experiments we showed that a peptide corresponding to MBM1 efficiently dissociates the menin-MLL complex. Altogether, our work establishes the molecular basis of the menin interaction with MLL and MLL fusion proteins and provides the necessary foundation for development of small molecule inhibitors targeting this interaction in leukemias with MLL translocations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.