{"doi":"10.1101/2025.04.07.647605","title":"TTLL4 glutamyltransferase is a therapeutic target for NPM1-mutated acute myeloid leukemia","abstract":"Abstract NPM1-mutated acute myeloid leukemia (AML) is defined by aberrant cytoplasmic localization of the mutant NPM1c protein, and therapeutic strategies targeting this specific disease remain limited. Here, we identify TTLL4, a mono-glutamate glutamyltransferase, as a selective vulnerability in NPM1c AML. TTLL4 catalyzes post-translational hyper-glutamylation of NPM1c at E126, stabilizes its cytoplasmic localization and promotes a differentiation block in leukemic cells. Multiple genetic TTLL4 inactivation approaches in human NPM1c-mutant cell lines reduce NPM1c glutamylation, trigger myeloid differentiation, and impair proliferation. Transcriptomic analyses show that TTLL4 knockdown pheno-copies NPM1c degradation and aligns with KMT2A and XPO1-targeted gene expression programs. Furthermore, Ttll4 knockout significantly prolonged survival in an NPM1c/NRAS-driven mouse AML model and promoted differentiation. We identify a small molecule, EN7, that selectively inhibits TTLL4 and recapitulates these phenotypes in NPM1c + cells. These findings identify glutamylation as a new axis of leukemic regulation and highlight TTLL4 as a druggable epigenetic regulator in NPM1c AML.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":563995,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"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":1166201,"name":"Humaira Ilyas","orcid":"0000-0002-5784-9086","position":1,"is_corresponding":false},{"id":247700,"name":"Maxim I. Maron","orcid":"0000-0001-7809-5888","position":2,"is_corresponding":false},{"id":685256,"name":"Subray S. Hegde","orcid":"0000-0002-1947-5917","position":3,"is_corresponding":false},{"id":1294050,"name":"Melissa R. Leyden","orcid":"0009-0006-4402-5236","position":4,"is_corresponding":false},{"id":1466825,"name":"Irene Mariam Roy","orcid":"0000-0002-9858-1207","position":5,"is_corresponding":false},{"id":1467179,"name":"Rotila Hyka","orcid":null,"position":6,"is_corresponding":false},{"id":1214881,"name":"Lucas Dada","orcid":"0000-0001-5846-0219","position":7,"is_corresponding":false},{"id":267554,"name":"Jeffrey Shabanowitz","orcid":"0000-0001-5750-3539","position":8,"is_corresponding":false},{"id":267543,"name":"Donald F. Hunt","orcid":"0000-0003-2815-6368","position":9,"is_corresponding":false},{"id":1399130,"name":"Ellen Angeles","orcid":"0000-0002-5081-6599","position":10,"is_corresponding":false},{"id":990950,"name":"Victor Morell","orcid":"0000-0002-7071-1030","position":11,"is_corresponding":false},{"id":488126,"name":"Benjamin M. Lorton","orcid":"0000-0002-8553-2078","position":12,"is_corresponding":false},{"id":586703,"name":"Shira Glushakow-Smith","orcid":"0000-0002-6012-7236","position":13,"is_corresponding":false},{"id":849173,"name":"Daniel K. Borger","orcid":"0000-0001-8055-019X","position":14,"is_corresponding":false},{"id":1397684,"name":"Yuxuan Wang","orcid":"0000-0001-6476-9589","position":15,"is_corresponding":false},{"id":245085,"name":"Linde A. Miles","orcid":"0000-0003-3578-2842","position":16,"is_corresponding":false},{"id":830325,"name":"Roger Belizaire","orcid":"0000-0001-8496-287X","position":17,"is_corresponding":false},{"id":563491,"name":"Seiya Kitamura","orcid":"0000-0003-2453-849X","position":18,"is_corresponding":false},{"id":586706,"name":"Kira Gritsman","orcid":"0000-0002-1367-1167","position":19,"is_corresponding":false},{"id":488128,"name":"David Shechter","orcid":"0000-0001-9388-6004","position":20,"is_corresponding":false},{"id":292724,"name":"Alexandra Schurer","orcid":"0000-0001-8028-838X","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:17.117043Z","pmid":null,"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":[]}