biostudies-literatureBravo-Perez CVera and Joseph Dresner FoundationInstituto de Salud Carlos IIIEuropean Research CouncilNational Heart, Lung, and Blood InstituteSigrid Juselius FoundationCancer Foundation FinlandVeloSanoERA PerMedAcademy of Finland Heal-Art consortiumAplastic Anemia and MDS International FoundationEdward P. Evans Foundatione184431https://www.ebi.ac.uk/biostudies/studies/S-EPMC12043085biostudies-literatureUnknown135(9)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 tThe Journal of clinical investigationInborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia.PMC12043085JR22/00041NAJAKSTAT-TARGET consortium647355M-IMM 647355R35HL135795314442Ogbue OOrland MKawashima NKubota YGuarnera LBrady ZWitt MHuuhtanen JMandala AVisconte VPagliuca SMustjoki SWilliams NDUnlu SDurmaz ABravo-Perez CAhmed AHaddad CGurnari CMaciejewski JPfalseInborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia.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 t2025-01-01T00:00:00Z2025 May2026-06-01T10:17:11.428Z2025-07-08T03:12:48.886ZS-EPMC120430854030977010.1172/JCI184431