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Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)\/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effect of ruxolitinib on primary human CLL cells was studied <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells <jats:italic>in vitro<\/jats:italic>. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7\/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited  TLR-mediated <jats:italic>IL10<\/jats:italic> transcription and markedly reduced IL-10 production <jats:italic>in vitro<\/jats:italic>. It also decreased blood levels of IL-10 while increasing TNF\u03b1 along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells <jats:italic>in vivo<\/jats:italic>. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production <jats:italic>in vitro<\/jats:italic> but, in contrast to ruxolitinib, blocked initial <jats:italic>IL10<\/jats:italic> transcription induced by TLR-signaling in vitro, decreased TNF\u03b1 production, and deactivates CLL cells <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NF\u03baB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1043694","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T05:16:25Z","timestamp":1681190185000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo"],"prefix":"10.3389","volume":"13","author":[{"given":"David E.","family":"Spaner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina 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