{"doi":"10.1172/jci184431","title":"Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia","abstract":"BACKGROUNDT cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents a unique model for the study of persistent CTL expansions. Albeit autoimmunity is implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL.METHODSThis is a comprehensive immunogenomic study of 92 consecutive patients from a large T-LGLL cohort with full laboratory-clinical characterization (n = 271). Whole-exome profiling of variants associated with inborn errors of immunity (IEI) and somatic mutations in T cell lymphoid drivers was analyzed. Single-cell RNA-Seq and TCR-Seq in T-LGLL samples and RNA-Seq in T cell cancer cell lines were utilized to establish biological correlations.RESULTSLymphocytopenia and/or hypogammaglobulinemia were identified in 186 of 241 (77%) T-LGLL patients. Genetic screening for IEI revealed 43 rare heterozygous variants in 38 different immune genes in 34 of 92 (36%) patients (vs. 167/63,026 [0.26%] in controls). High-confidence deleterious variants associated with dominant, adult-onset IEIs were detected in 15 of 92 (16%) patients. Carriers showed atypical features otherwise tied to the cryptic IEI, such as earlier onset, lower lymphocyte counts, lower STAT3 mutational rate, and higher proportions of hypogammaglobulinemia and immune cytopenia/bone marrow failure than noncarriers. Somatic mutational landscape, RNA-Seq, and TCR-Seq analyses supported immune imbalance caused by the IEI variants and interactions with somatic mutations in T cell lymphoid drivers.CONCLUSIONSOur findings in T-LGLL reveal that maladaptive CTL expansions may stem from cryptic immunodeficiency traits and open the horizon of IEIs to clonal hematopoiesis and bone marrow failure.FUNDINGNIH; Aplastic Anemia and MDS International Foundation; VeloSano; Edward P. Evans Foundation; Instituto de Salud Carlos III; European Research Council; European Research Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.","journal":"Journal of Clinical Investigation","year":2025,"id":533626,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"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":567512,"name":"Carmelo Gurnari","orcid":"0000-0001-6829-5544","position":1,"is_corresponding":false},{"id":990835,"name":"Jani Huuhtanen","orcid":"0000-0003-2750-4033","position":2,"is_corresponding":false},{"id":1410808,"name":"Naomi Kawashima","orcid":"0000-0002-9914-739X","position":3,"is_corresponding":false},{"id":1233869,"name":"Luca Guarnera","orcid":"0000-0001-8293-0663","position":4,"is_corresponding":false},{"id":1358725,"name":"Aashray Mandala","orcid":null,"position":5,"is_corresponding":false},{"id":1410807,"name":"Nakisha D Williams","orcid":"0000-0001-8279-6476","position":6,"is_corresponding":false},{"id":1411216,"name":"Christopher Haddad","orcid":null,"position":7,"is_corresponding":false},{"id":1415836,"name":"Michaela Witt","orcid":null,"position":8,"is_corresponding":false},{"id":79009,"name":"Serhan Ünlü","orcid":"0000-0002-0425-5030","position":9,"is_corresponding":false},{"id":1358724,"name":"Zachary Brady","orcid":null,"position":10,"is_corresponding":false},{"id":1410809,"name":"Olisaemeka Ogbue","orcid":"0000-0001-9614-6626","position":11,"is_corresponding":false},{"id":1415403,"name":"Mark Orland","orcid":"0000-0002-1842-6187","position":12,"is_corresponding":false},{"id":1411215,"name":"Arooj Ahmed","orcid":null,"position":13,"is_corresponding":false},{"id":908952,"name":"Yasuo Kubota","orcid":"0000-0002-7909-5422","position":14,"is_corresponding":false},{"id":323643,"name":"Simona Pagliuca","orcid":"0000-0003-4688-2478","position":15,"is_corresponding":false},{"id":261746,"name":"Arda Durmaz","orcid":"0000-0001-8394-600X","position":16,"is_corresponding":false},{"id":638123,"name":"Satu Mustjoki","orcid":"0000-0002-0816-8241","position":17,"is_corresponding":false},{"id":348416,"name":"Valeria Visconte","orcid":"0000-0002-2993-1509","position":18,"is_corresponding":false},{"id":32731,"name":"Jaroslaw P. 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