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Through RNA-Sequencing of purified T-LGLs we reveal gene expression profiles and pathway dysregulations in the major patient subgroups, defined by CD8+ or CD4+ phenotype and\n                    <jats:italic>STAT3<\/jats:italic>\n                    \/\n                    <jats:italic>STAT5B<\/jats:italic>\n                    mutational status. Overall, T-LGLL patients exhibited a marked transcriptome dysregulation compared to controls. This was more pronounced in the most symptomatic CD8\u2009+\u2009\n                    <jats:italic>STAT3<\/jats:italic>\n                    -mutated patients, which emerged as a distinct biological entity, separated from the other disease subgroups. Particularly, CD8\u2009+\u2009\n                    <jats:italic>STAT3<\/jats:italic>\n                    -mutated cases displayed extensive down-regulation of genes, ultimately resulting in the de-repression of proliferation and cell cycle pathways. Among genes up-regulated in CD8\u2009+\u2009\n                    <jats:italic>STAT3<\/jats:italic>\n                    -mutated cases we found\n                    <jats:italic>VCAM1<\/jats:italic>\n                    , the transcriptional repressor EZH2 and the p53-regulator MDM2 proto-oncogene, as well as the leukemogenesis-associated\n                    <jats:italic>PVT1<\/jats:italic>\n                    up-regulation, representing the first report of a long-non-coding RNA alterations in leukemic T-LGLs. The impact of\n                    <jats:italic>STAT5B<\/jats:italic>\n                    mutations on T-LGLs transcriptome was more limited and the overexpression of the\n                    <jats:italic>PIM1<\/jats:italic>\n                    serine\/threonine kinase proto-oncogene was identified as one of the most relevant features of\n                    <jats:italic>STAT5B<\/jats:italic>\n                    -mutated CD4\u2009+\u2009T-LGLL. This study significantly advances our understanding of T-LGLL pathogenesis, uncovering new oncogenic mechanisms within the distinct molecular subtypes of the disease.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02708-1","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T06:23:33Z","timestamp":1753683813000},"page":"2364-2374","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Transcriptomic landscape of CD8+ and CD4\u2009+\u2009T-LGL leukemia revealed the distinct impact of STAT3 and STAT5B activating mutations"],"prefix":"10.1038","volume":"39","author":[{"given":"Giulia","family":"Calabretto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Binatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Teramo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Buratin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Baril\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8689-3759","authenticated-orcid":false,"given":"Vanessa Rebecca","family":"Gasparini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Vicenzetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6338-7677","authenticated-orcid":false,"given":"Enrico","family":"Gaffo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Rampazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8860-5875","authenticated-orcid":false,"given":"Silvia","family":"Orsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Buson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Trimarco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Mariotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0100-5789","authenticated-orcid":false,"given":"Monica","family":"Facco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-8012","authenticated-orcid":false,"given":"Flavia","family":"Bazzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Trentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6061-4595","authenticated-orcid":false,"given":"Gianpietro","family":"Semenzato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8799-5324","authenticated-orcid":false,"given":"Renato","family":"Zambello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8240-3070","authenticated-orcid":false,"given":"Stefania","family":"Bortoluzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"2708_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1182\/blood.V82.1.1.bloodjournal8211","volume":"82","author":"TP Loughran Jr","year":"1993","unstructured":"Loughran TP Jr. Clonal diseases of large granular lymphocytes. 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