{"doi":"10.1002/ijc.35332","title":"Targeting the Menin–KMT2A interaction in leukemia: Lessons learned and future directions","abstract":"Chromosomal rearrangements involving the Mixed Lineage Leukemia gene (MLL1, KMT2A) are defining a genetically distinct subset in about 10% of human acute leukemias. Translocations involving the KMT2A-locus at chromosome 11q23 are resulting in the formation of a chimeric oncogene, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The most frequently found fusion partners of KMT2A in acute leukemia are the C-terminal parts of AFF1, MLLT3, MLLT1 and MLLT10. Unfortunately, the presence of an KMT2A-rearrangements is associated with adverse outcomes in leukemia patients. Moreover, non-rearranged KMT2A-complexes have been demonstrated to be crucial for disease development and maintenance in NPM1-mutated and NUP98-rearranged leukemia, expanding the spectrum of genetic disease subtypes that are dependent on KMT2A. Recent advances in the development of targeted therapy strategies to disrupt the function of KMT2A-complexes in leukemia have led to the establishment of Menin-KMT2A interaction inhibitors that effectively eradicate leukemia in preclinical model systems and show favorable tolerability and significant efficacy in early-phase clinical trials. Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A-rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A-complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors.","journal":"International Journal of Cancer","year":2025,"id":510564,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":239030,"name":"Jayant Y. Gadrey","orcid":null,"position":1,"is_corresponding":false},{"id":236907,"name":"Scott A. Armstrong","orcid":"0000-0002-9099-4728","position":2,"is_corresponding":false},{"id":1026765,"name":"Michael W.M. Kühn","orcid":"0000-0002-6434-9303","position":3,"is_corresponding":false},{"id":481407,"name":"Florian Perner","orcid":"0000-0003-1010-3321","position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":null,"created_at":"2026-07-19T02:47:36.538276Z","pmid":"39887730","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}