{"doi":"10.1101/2025.10.13.681683","title":"Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML","abstract":"ABSTRACT Acute myeloid leukemia (AML) harboring MLL ( MLL1, KMT2A ) rearrangement ( MLL-r ) remains a lethal subtype with limited durable responses to single-agent menin inhibition. To define rational combination strategies, we performed a high-throughput screen of >900 epigenetic modulators in combination with menin inhibition in MLL-r AML models. This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat. Mechanistically, LSD1 was found to interact with LEDGF/p75 (PSIP1), a chromatin-anchoring cofactor of the menin-MLL complex at H3K36me3 marked euchromatin. Chromatin profiling revealed extensive co-occupancy of LSD1 and menin-MLL components at leukemogenic loci in MLL-r AML cells. Dual inhibition of menin and LSD1 dismantled this chromatin complex, evicted H3K36me3 from LEDGF-bound sites, and reprogrammed transcription toward myeloid differentiation. Combined menin and LSD1 blockade repressed canonical MLL targets, including HOXA9, MYC, FLT3, PBX3 , and CDK6 , while restoring H3K36me3 and H3K4me3 and activating differentiation-associated genes. In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559314,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"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":320514,"name":"Helena G. Dos Santos","orcid":"0000-0002-9671-4272","position":1,"is_corresponding":false},{"id":265865,"name":"Felipe Beckedorff","orcid":"0000-0001-6735-6851","position":2,"is_corresponding":false},{"id":908948,"name":"Tulasigeri M. Totiger","orcid":"0000-0002-4262-4458","position":3,"is_corresponding":false},{"id":307350,"name":"Adnan K. Mookhtiar","orcid":"0000-0002-5110-4518","position":4,"is_corresponding":false},{"id":1461130,"name":"Anna Lesley Kingham","orcid":null,"position":5,"is_corresponding":false},{"id":1402013,"name":"Guilherme Miura Lavezzo","orcid":"0000-0002-8709-354X","position":6,"is_corresponding":false},{"id":602050,"name":"Glòria Mas Martín","orcid":"0000-0003-0730-3541","position":7,"is_corresponding":false},{"id":503527,"name":"Hsuan-Ting Huang","orcid":"0000-0003-0383-8020","position":8,"is_corresponding":false},{"id":1443578,"name":"Efe Karaca","orcid":"0000-0003-4109-6013","position":9,"is_corresponding":false},{"id":675334,"name":"Daniel Bilbao","orcid":"0000-0003-1630-8811","position":10,"is_corresponding":false},{"id":309200,"name":"Justin Taylor","orcid":"0000-0003-4407-6325","position":11,"is_corresponding":false},{"id":44604,"name":"Ramin Shiekhattar","orcid":"0000-0002-7943-7277","position":12,"is_corresponding":false},{"id":309199,"name":"Justin M. Watts","orcid":"0000-0001-5213-5482","position":13,"is_corresponding":false},{"id":678804,"name":"Mina M. Tayari","orcid":"0000-0003-3521-8782","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41279447","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":[]}