دورية أكاديمية
Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis.
| العنوان: | Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis. |
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| المؤلفون: | Keenan C; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Albeituni S; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Oak N; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Stroh A; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Tillman HS; Department of Comparative Pathology Core, St. Jude Children's Research Hospital, Memphis, TN., Wang Y; Preclinical PK Shared Resource, St. Jude Children's Research Hospital, Memphis, TN., Freeman BB 3rd; Preclinical PK Shared Resource, St. Jude Children's Research Hospital, Memphis, TN., Alemán-Arteaga S; Experimental Therapeutics & Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain., Meyer LK; Department of Pediatrics, University of Washington, Seattle, WA., Woods R; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Verbist KC; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN., Zhou Y; Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN., Cheng C; Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN., Nichols KE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN. |
| المصدر: | Blood [Blood] 2024 Jun 06; Vol. 143 (23), pp. 2386-2400. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Nitriles* , Pyrimidines*/pharmacology , Lymphohistiocytosis, Hemophagocytic*/drug therapy , Lymphohistiocytosis, Hemophagocytic*/chemically induced , Lymphohistiocytosis, Hemophagocytic*/pathology , Pyrazoles*/pharmacology , Pyrazoles*/therapeutic use , Disease Models, Animal*, Animals ; Mice ; Janus Kinase 1/antagonists & inhibitors ; Janus Kinase 1/metabolism ; Janus Kinase 1/genetics ; Pyrroles/pharmacology ; Pyrroles/therapeutic use ; Janus Kinase 2/antagonists & inhibitors ; Janus Kinase 2/genetics ; Janus Kinase 2/metabolism ; Mice, Inbred C57BL ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; STAT1 Transcription Factor/metabolism ; STAT1 Transcription Factor/genetics ; Janus Kinase Inhibitors/pharmacology ; Janus Kinase Inhibitors/therapeutic use ; Piperidines/pharmacology ; Humans ; Benzenesulfonamides ; Bridged-Ring Compounds ; Pyrrolidines |
| مستخلص: | Abstract: 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 were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-γ)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1-/-) 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-/- 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. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.) |
| المشرفين على المادة: | 82S8X8XX8H (ruxolitinib) 0 (Nitriles) 0 (Pyrimidines) 0 (Pyrazoles) 0 (11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene) 6L1XP550I6 (fedratinib) EC 2.7.10.2 (Janus Kinase 1) 0 (Pyrroles) EC 2.7.10.2 (Janus Kinase 2) 0 (Sulfonamides) 0 (STAT1 Transcription Factor) 0 (Janus Kinase Inhibitors) EC 2.7.10.2 (Jak2 protein, mouse) 0 (Piperidines) EC 2.7.10.2 (Jak1 protein, mouse) 0 (Stat1 protein, mouse) 0 (Benzenesulfonamides) 0 (Bridged-Ring Compounds) 0 (Pyrrolidines) |
| تواريخ الأحداث: | Date Created: 20240306 Date Completed: 20240606 Latest Revision: 20240606 |
| رمز التحديث: | 20240606 |
| DOI: | 10.1182/blood.2023021046 |
| PMID: | 38446698 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2023021046 |