{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:10:54Z","timestamp":1778688654667,"version":"3.51.4"},"reference-count":91,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG-20216"],"award-info":[{"award-number":["IG-20216"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration\/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK\/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.<\/jats:p>","DOI":"10.3390\/cells10102800","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T01:23:46Z","timestamp":1634693026000},"page":"2800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Neutropenia and Large Granular Lymphocyte Leukemia: From Pathogenesis to Therapeutic Options"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8646-2932","authenticated-orcid":false,"given":"Giulia","family":"Calabretto","sequence":"first","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Teramo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3430-6115","authenticated-orcid":false,"given":"Gregorio","family":"Baril\u00e0","sequence":"additional","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Vicenzetto","sequence":"additional","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8689-3759","authenticated-orcid":false,"given":"Vanessa Rebecca","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianpietro","family":"Semenzato","sequence":"additional","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renato","family":"Zambello","sequence":"additional","affiliation":[{"name":"Department of Medicine, Padua University School of Medicine, 35129 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/blood.V82.1.1.bloodjournal8211","article-title":"Clonal Diseases of Large Granular Lymphocytes","volume":"82","author":"Loughran","year":"1993","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e455","DOI":"10.1038\/bcj.2016.59","article-title":"A Population-Based Study of Large Granular Lymphocyte Leukemia","volume":"6","author":"Shah","year":"2016","journal-title":"Blood Cancer J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1038\/leu.2016.68","article-title":"Population-Based Analyses among 184 Patients Diagnosed with Large Granular Lymphocyte Leukemia in the Netherlands between 2001 and 2013","volume":"30","author":"Dinmohamed","year":"2016","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/ijlh.12817","article-title":"The 2017 WHO Update on Mature T- and Natural Killer (NK) Cell Neoplasms","volume":"40","author":"Matutes","year":"2018","journal-title":"Int. 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