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Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T [greater than] C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-[kappa]B more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-[alpha] and interferon (IFN)-[gamma], which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-[kappa]B, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-[kappa]B from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS., Author(s): Haijun Wen [1, 2, 3]; Huajuan Ma [1, 4]; Qichun Cai [1, 5, 6]; Suxia Lin [1, 7]; Xinxing Lei [1]; Bin He [1]; Sijin Wu [8]; Zifeng Wang [...]

Background: Hippo‐Yes‐associated protein (YAP) pathway plays an important role in epithelial cell proliferation and development. However, its possible role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown. We aim to investigate it on nasal epithelial proliferation and remodeling in CRSwNP. Methods: The expressions of hippo pathway components as well as Ki‐67 and E‐cadherin in the sinonasal mucosa and nasal epithelial cells were analyzed in 14 controls, 14 eosinophilic CRSwNP, and 14 noneosinophilic CRSwNP. Nasal epithelial cells from 6 controls, 6 eosinophilic CRSwNP, and 6 noneosinophilic CRSwNP were cultured and treated with lipopolysaccharide (LPS), Poly(I:C), or a selective YAP inhibitor verteporfin (VP). Results: The hippo pathway components MST1, LATS1/2, YAP, and TEAD1 were increased in both eosinophilic and noneosinophilic CRSwNP, particularly in nasal epithelial cells, along with upregulation of Ki‐67 and downregulation of E‐cadherin. The mRNA levels of YAP positively correlated with the Ki‐67 mRNA levels, and negatively associated with the E‐cadherin mRNA levels in polyp tissues and epithelial cells from nasal polyps (NPECs). LPS and Poly(I:C) upregulated the YAP expression in nasal epithelial cells accompanied by increased TEAD1 and Ki‐67 expression. Conversely, YAP inhibition by VP decreased TEAD1 and Ki‐67 expression in NPECs. Conclusions: Hippo pathway components are abnormally upregulated in NPECs, and its effector YAP promotes nasal epithelial cells proliferation and remodeling in CRSwNP. It provides a rationale to explore inhibition of YAP as a novel therapeutic strategy for reducing the epithelial proliferation and remodeling in CRSwNP. Hippo pathway is aberrantly expressed in nasal polyps. Hippo pathway effector Yes‐associated protein is involved in epithelial proliferation and remodeling in nasal polyps. Inhibition of Yes‐associated protein can reduce proliferation of nasal polyp epithelial cells. [ABSTRACT FROM AUTHOR]