{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T10:54:31Z","timestamp":1794308071764,"version":"4.9.0"},"reference-count":40,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,12,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative disorder characterized by an expansion of clonal T or natural killer lymphocytes. Neutropenia-related infections and anemia represent the main manifestations. LGL leukemia is frequently associated with autoimmune disorders such as rheumatoid arthritis, Sj\u00f6gren's syndrome, autoimmune endocrinopathies, vasculitis, or autoimmune cytopenia. Recent advances in the phenotypic and molecular characterization of LGL clones have underscored the pivotal role of a chronic antigenic stimulation and a dysregulation of the Jak\/STAT signaling pathway in the pathophysiology linking leukemic-cell expansion and autoimmunity. In more than half of patients, there is a somatic STAT3 mutation. The disease is characterized by an indolent course, but approximately half of all patients will eventually require therapy. The first-line treatment for LGL leukemia is historically based on immunosuppressive agents (methotrexate, cyclophosphamide, or cyclosporine). However, cytokines blocking molecules or Jak\/STAT inhibitors represent a new conceptual therapeutic approach for LGL leukemia. In this review, we present an overview of the spectrum of LGL proliferations, potential links between LGL expansion and autoimmunity, and therapeutic approaches.<\/jats:p>","DOI":"10.1182\/hematology.2024000539","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T10:02:08Z","timestamp":1733479328000},"page":"143-149","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":19,"title":["Large granular lymphocyte leukemia: a clonal disorder with autoimmune manifestations"],"prefix":"10.1182","volume":"2024","author":[{"given":"Tony","family":"Marchand","sequence":"first","affiliation":[{"name":"1 Service d'H\u00e9matologie Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France"},{"name":"2 Universit\u00e9 de Rennes, Rennes, France"},{"name":"3 UMR 1236, Rennes University, INSERM, \u00c9tablissement Fran\u00e7ais du Sang Bretagne, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Pastoret","sequence":"additional","affiliation":[{"name":"3 UMR 1236, Rennes University, INSERM, \u00c9tablissement Fran\u00e7ais du Sang Bretagne, Rennes, France"},{"name":"4 Laboratoire d'H\u00e9matologie, Centre Hospitalier Universitaire de Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Moignet","sequence":"additional","affiliation":[{"name":"1 Service d'H\u00e9matologie Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Roussel","sequence":"additional","affiliation":[{"name":"2 Universit\u00e9 de Rennes, Rennes, France"},{"name":"3 UMR 1236, Rennes University, INSERM, \u00c9tablissement Fran\u00e7ais du Sang Bretagne, Rennes, France"},{"name":"4 Laboratoire d'H\u00e9matologie, Centre Hospitalier Universitaire de Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Lamy","sequence":"additional","affiliation":[{"name":"1 Service d'H\u00e9matologie Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France"},{"name":"2 Universit\u00e9 de Rennes, Rennes, France"},{"name":"3 UMR 1236, Rennes University, INSERM, \u00c9tablissement Fran\u00e7ais du Sang Bretagne, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"issue":"3","key":"2024121115354734300_hem2024000539C1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1365-2141.2007.06564.x","article-title":"The expression of the novel cytotoxic protein granzyme M by large granular lymphocytic leukaemias of both T-cell and NK-cell lineage: an unexpected finding with implications regarding the pathobiology of these disorders","volume":"137","author":"Morice","year":"2007","journal-title":"Br J Haematol"},{"issue":"9","key":"2024121115354734300_hem2024000539C2","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.3324\/haematol.2009.018481","article-title":"Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases","volume":"95","author":"Bareau","year":"2010","journal-title":"Haematologica"},{"issue":"11","key":"2024121115354734300_hem2024000539C3","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1182\/blood.2022015851","article-title":"The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee","volume":"140","author":"Campo","year":"2022","journal-title":"Blood"},{"issue":"7","key":"2024121115354734300_hem2024000539C4","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"issue":"1","key":"2024121115354734300_hem2024000539C5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1182\/blood.V89.1.256","article-title":"The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis","volume":"89","author":"Semenzato","year":"1997","journal-title":"Blood"},{"issue":"3","key":"2024121115354734300_hem2024000539C6","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/sj.leu.2404112","article-title":"TCRgammadelta+ large granular lymphocyte leukemias reflect the spectrum of normal antigen-selected TCRgammadelta+ T-cells","volume":"20","author":"Sandberg","year":"2006","journal-title":"Leukemia"},{"issue":"1","key":"2024121115354734300_hem2024000539C7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1182\/blood.V98.1.165","article-title":"Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCRalphabeta T-cell proliferations","volume":"98","author":"Langerak","year":"2001","journal-title":"Blood"},{"issue":"3","key":"2024121115354734300_hem2024000539C8","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1111\/bjh.19252","article-title":"Evaluation of T-cell clonality by anti-TRBC1 antibody-based flow cytometry and correlation with T-cell receptor sequencing","volume":"204","author":"Nguyen","year":"2024","journal-title":"Br J Haematol"},{"issue":"23","key":"2024121115354734300_hem2024000539C9","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.1182\/blood.2020006721","article-title":"Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells","volume":"137","author":"Pastoret","year":"2021","journal-title":"Blood"},{"issue":"10","key":"2024121115354734300_hem2024000539C10","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1038\/s41379-020-0568-2","article-title":"T-cell clones of uncertain significance are highly prevalent and show close resemblance to T-cell large granular lymphocytic leukemia. Implications for laboratory diagnostics","volume":"33","author":"Shi","year":"2020","journal-title":"Mod Pathol"},{"issue":"3","key":"2024121115354734300_hem2024000539C11","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1172\/JCI9940","article-title":"Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression","volume":"107","author":"Epling-Burnette","year":"2001","journal-title":"J Clin Invest"},{"issue":"20","key":"2024121115354734300_hem2024000539C12","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1182\/blood.2021013164","article-title":"Genomic landscape of TCR\u03b1\u03b2 and TCR\u03b3\u03b4 T-large granular lymphocyte leukemia","volume":"139","author":"Cheon","year":"2022","journal-title":"Blood"},{"issue":"15","key":"2024121115354734300_hem2024000539C13","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1182\/blood-2012-06-435297","article-title":"STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia","volume":"120","author":"Jerez","year":"2012","journal-title":"Blood"},{"issue":"20","key":"2024121115354734300_hem2024000539C14","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1056\/NEJMoa1114885","article-title":"Somatic STAT3 mutations in large granular lymphocytic leukemia","volume":"366","author":"Koskela","year":"2012","journal-title":"N Engl J Med"},{"issue":"12","key":"2024121115354734300_hem2024000539C15","doi-asserted-by":"crossref","first-page":"3508","DOI":"10.3390\/cancers12123508","article-title":"STAT3 and STAT5B mutations in T\/NK-cell chronic lymphoproliferative disorders of large granular lymphocytes (LGL): association with disease features","volume":"12","author":"Mu\u00f1oz-Garc\u00eda","year":"2020","journal-title":"Cancers (Basel)"},{"issue":"22","key":"2024121115354734300_hem2024000539C16","doi-asserted-by":"crossref","first-page":"4541","DOI":"10.1182\/blood-2012-12-474577","article-title":"Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia","volume":"121","author":"Rajala","year":"2013","journal-title":"Blood"},{"issue":"8","key":"2024121115354734300_hem2024000539C17","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1182\/blood.2020005831","article-title":"Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias","volume":"138","author":"Olson","year":"2021","journal-title":"Blood"},{"issue":"5","key":"2024121115354734300_hem2024000539C18","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41588-022-01059-2","article-title":"CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk","volume":"54","author":"Baer","year":"2022","journal-title":"Nat Genet"},{"issue":"1","key":"2024121115354734300_hem2024000539C19","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1038\/s41467-022-29173-z","article-title":"Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia","volume":"13","author":"Huuhtanen","year":"2022","journal-title":"Nat Commun"},{"issue":"1","key":"2024121115354734300_hem2024000539C20","first-page":"163","article-title":"Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia","volume":"109","author":"Vicenzetto","year":"2023","journal-title":"Haematologica"},{"issue":"3","key":"2024121115354734300_hem2024000539C21","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1080\/1744666X.2023.2292758","article-title":"The complex relationship between large granular lymphocyte leukemia and rheumatic disease","volume":"20","author":"Marchand","year":"2024","journal-title":"Expert Rev Clin Immunol"},{"issue":"7","key":"2024121115354734300_hem2024000539C22","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1002\/ajh.26183","article-title":"Large granular lymphocytic leukemia\u2014a retrospective study of 319 cases","volume":"96","author":"Dong","year":"2021","journal-title":"Am J Hematol"},{"issue":"2","key":"2024121115354734300_hem2024000539C23","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1080\/10428194.2017.1339880","article-title":"Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL)","volume":"59","author":"Sanikommu","year":"2018","journal-title":"Leuk Lymphoma"},{"issue":"21","key":"2024121115354734300_hem2024000539C24","doi-asserted-by":"crossref","first-page":"13345","DOI":"10.3390\/ijms232113345","article-title":"Clinical study of the relationship between Sj\u00f6gren syndrome and T-cell large granular lymphocytic leukemia: single-center experience","volume":"23","author":"Gorodetskiy","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"6","key":"2024121115354734300_hem2024000539C25","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1016\/j.chest.2020.07.094","article-title":"Large granular lymphocyte leukemia and precapillary pulmonary hypertension","volume":"158","author":"Cherel","year":"2020","journal-title":"Chest"},{"issue":"3","key":"2024121115354734300_hem2024000539C26","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/j.1365-2133.2007.08035.x","article-title":"Cutaneous vasculitis and T-large granular lymphocyte leukaemia with parallel evolution","volume":"157","author":"Meyer","year":"2007","journal-title":"Br J Dermatol"},{"issue":"3","key":"2024121115354734300_hem2024000539C27","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.semarthrit.2013.07.002","article-title":"Vasculitis associated with large granular lymphocyte (LGL) leukemia: presentation and treatment outcomes of 11 cases","volume":"43","author":"Audemard","year":"2013","journal-title":"Semin Arthritis Rheum"},{"key":"2024121115354734300_hem2024000539C28","doi-asserted-by":"crossref","first-page":"15869","DOI":"10.1038\/ncomms15869","article-title":"Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis","volume":"8","author":"Savola","year":"2017","journal-title":"Nat Commun"},{"issue":"1","key":"2024121115354734300_hem2024000539C29","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3324\/haematol.2014.113142","article-title":"The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia","volume":"100","author":"Rajala","year":"2015","journal-title":"Haematologica"},{"issue":"4","key":"2024121115354734300_hem2024000539C30","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.jaci.2022.09.002","article-title":"Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome","volume":"151","author":"Leiding","year":"2023","journal-title":"J Allergy Clin Immunol"},{"issue":"12","key":"2024121115354734300_hem2024000539C31","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1016\/j.immuni.2022.11.001","article-title":"STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation","volume":"55","author":"Masle-Farquhar","year":"2022","journal-title":"Immunity"},{"issue":"4","key":"2024121115354734300_hem2024000539C32","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/leu.2014.298","article-title":"Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998)","volume":"29","author":"Loughran","year":"2015","journal-title":"Leukemia"},{"issue":"suppl 1","key":"2024121115354734300_hem2024000539C33","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1182\/blood-2019-123439","article-title":"Prospective, multicentric phase II randomized trial comparing the efficacy of methotrexate or cyclophosphamide in large granular lymphocytic leukemia: a French national study. Report on the interim analysis","volume":"134","author":"Lamy","year":"2019","journal-title":"Blood"},{"issue":"8","key":"2024121115354734300_hem2024000539C34","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1182\/bloodadvances.2021006263","article-title":"Cyclophosphamide induces durable molecular and clinical responses in patients with relapsed T-LGL leukemia","volume":"6","author":"Braunstein","year":"2022","journal-title":"Blood Adv"},{"issue":"1","key":"2024121115354734300_hem2024000539C35","doi-asserted-by":"crossref","first-page":"e22","DOI":"10.1016\/S2352-3026(15)00227-6","article-title":"Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study","volume":"3","author":"Dumitriu","year":"2016","journal-title":"Lancet Haematol"},{"issue":"9","key":"2024121115354734300_hem2024000539C36","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s00277-013-1746-9","article-title":"Bendamustine salvage therapy for T cell neoplasms","volume":"92","author":"Zaja","year":"2013","journal-title":"Ann Hematol"},{"issue":"12","key":"2024121115354734300_hem2024000539C37","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1038\/leu.2015.280","article-title":"Tofacitinib as a novel salvage therapy for refractory T-cell large granular lymphocytic leukemia","volume":"29","author":"Bilori","year":"2015","journal-title":"Leukemia"},{"key":"2024121115354734300_hem2024000539C38","article-title":"Efficacy of ruxolitinib in the treatment of relapsed\/refractory large granular lymphocytic leukaemia [published online 19 April 2024]","author":"Marchand","journal-title":"Br J Haematol"},{"issue":"suppl 1","key":"2024121115354734300_hem2024000539C39","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1182\/blood-2023-181922","article-title":"Ruxolitinib promotes clinical responses in large granular lymphocytic leukemia via suppression of JAK\/STAT-dependent inflammatory cascades","volume":"142","author":"Moskowitz","year":"2023","journal-title":"Blood"},{"issue":"15","key":"2024121115354734300_hem2024000539C40","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1182\/blood.2022017643","article-title":"Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia","volume":"142","author":"Brammer","year":"2023","journal-title":"Blood"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2024\/1\/143\/2346574\/143marchand.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2024\/1\/143\/2346574\/143marchand.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T14:39:51Z","timestamp":1733927991000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2024\/1\/143\/526187\/Large-granular-lymphocyte-leukemia-a-clonal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,6]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12,6]]},"published-print":{"date-parts":[[2024,12,6]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2024000539","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,12,6]]},"published":{"date-parts":[[2024,12,6]]}}}