{"doi":"10.1016/j.cell.2025.03.047","title":"Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias","abstract":"<h2>Summary</h2> Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8<sup>+</sup> T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in <i>CLK3</i> and <i>RHOT2</i> resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.","journal":"Cell","year":2025,"id":509308,"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":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"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":995440,"name":"Edie I. 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Belleville","orcid":"0000-0001-9549-4338","position":9,"is_corresponding":false},{"id":740444,"name":"Nina Fox","orcid":null,"position":10,"is_corresponding":false},{"id":1363215,"name":"Cynthia Castro","orcid":"0009-0002-7626-8903","position":11,"is_corresponding":false},{"id":410141,"name":"Pu Zhang","orcid":"0000-0003-4174-8202","position":12,"is_corresponding":false},{"id":1363216,"name":"Takeshi Fujino","orcid":"0000-0001-5862-1203","position":13,"is_corresponding":false},{"id":1363217,"name":"Jennifer Lewis","orcid":"0009-0009-9619-9731","position":14,"is_corresponding":false},{"id":557773,"name":"Jahan Rahman","orcid":"0000-0001-8755-5890","position":15,"is_corresponding":false},{"id":998382,"name":"Beatrice Zhang","orcid":"0000-0003-1636-600X","position":16,"is_corresponding":false},{"id":1364081,"name":"Jacob H. Winick","orcid":null,"position":17,"is_corresponding":false},{"id":638611,"name":"Alexander M. 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