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Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS\u2013mitogen-activated protein kinase, T-cell receptor (TCR)\u2013phospholipase C gamma 1 (PLCG1)\u2013nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)\u2013signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR\u2013PLCG1\u2013NFAT, JAK\u2013STAT and NF-\u03baB pathways. Folliculotropism and large-cell transformation were also examined.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>NFAT and nuclear factor kappa B (NF-\u03baB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-\u03baB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia\/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-\u03baB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications.<\/jats:p>\n                  <jats:p>What's already known about this topic?<\/jats:p>\n                  <jats:p>Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood.<\/jats:p>\n                  <jats:p>What does this study add?<\/jats:p>\n                  <jats:p>An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected.<\/jats:p>\n                  <jats:p>What is the translational message?<\/jats:p>\n                  <jats:p>These results could have important implications for the treatment of MF in the near future.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1111\/bjd.18098","type":"journal-article","created":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T10:29:50Z","timestamp":1556879390000},"page":"147-155","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-\u03baB and nuclear factor of activated T cells pathways"],"prefix":"10.1093","volume":"182","author":[{"given":"C.","family":"P\u00e9rez","sequence":"first","affiliation":[{"name":"Translational Hematopathology Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla IDIVAL Santander Spain"},{"name":"Centro de 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