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Notably, in 40% of patients, constitutive STAT3 activation is due to <jats:italic>STAT3<\/jats:italic> activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1\/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1\/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1\/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why <jats:italic>STAT3<\/jats:italic>-unmutated patients show hyperactive STAT3.<\/jats:p>","DOI":"10.1038\/s41375-021-01480-2","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T12:03:24Z","timestamp":1638792204000},"page":"983-993","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["miR-181a is a novel player in the STAT3-mediated survival network of TCR\u03b1\u03b2+ CD8+ T large granular lymphocyte leukemia"],"prefix":"10.1038","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6947-8905","authenticated-orcid":false,"given":"Jorn L. J. 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TPL and DJF have received honoraria from Kymera Therapeutics. There are no conflicts of interest with the work presented in this manuscript. All other authors declare no conflicts of interest with the work presented in this study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}