{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:01:53Z","timestamp":1792504913802,"version":"4.5.0"},"reference-count":42,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,6]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK\/STAT pathway. Indeed, the JAK1\/2 inhibitor ruxolitinib has demonstrated efficacy in preclinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, JAK2 inhibitor fedratinib, and JAK1\/2 inhibitor ruxolitinib. All 3 drugs\u00a0were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-\u03b3)\u2013induced STAT1 phosphorylation in\u00a0vitro and in\u00a0vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG\u2013induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1\u2212\/\u2212) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib, and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1\u2212\/\u2212 mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, whereas fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent proinflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023021046","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T17:56:21Z","timestamp":1709747781000},"page":"2386-2400","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":27,"title":["Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis"],"prefix":"10.1182","volume":"143","author":[{"given":"Camille","family":"Keenan","sequence":"first","affiliation":[{"name":"1Department of Oncology, St. Jude Children\u2019s Research Hospital, Memphis, 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