Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma

Abstract

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>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB 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)-α and interferon (IFN)-γ, 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-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB 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.

Network Bioinformatics Analysis Provides Insight into Drug Repurposing for COVID-2019

“…In addition, previous work suggests that lenalidomide, a derivative of thalidomide, can restore T cells motility leading to their activation 26 . Finally, it was also reported that thalidomide prevents NF-kB from binding to the promoters of its target genes, including TNF-alpha and IFN-Gamma thereby reducing excessive inflammatory response 27,28 . Altogether, based on these previous studies, the reported successful use of thalidomide by Chen et al 24 , and our analysis, we hypothesize that thalidomide can be effective against COVID-2019 by modifying favourably immune response of the infected patients against the virus ( Figure 5).…”

An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

“…The function of the MCIA complex is supported by the existence of CI deficiency in patients harboring mutations in genes encoding components of this complex ( Alston et al, 2016 ; Fassone et al, 2011 ; Mimaki et al, 2012 ; Nouws et al, 2010 ). So far, only one ECSIT mutation has been identified in human disease, the V140A variant that triggers hyperinflammation and promotes hyperphagocytic syndrome in extranodal natural killer/T cell lymphoma (ENKTL) ( Wen et al, 2018 ). Furthermore, ECSIT function has only been examined using downregulation in cell lines.…”

Correspondence: RecurrentGNAQmutation encoding T96S in natural killer/T cell lymphoma

“…It was of peculiar interest to us that the two GNAQ hotspot somatic mutations (p.T96S and p.Y101X) reported in this study were never reported in other NKTCL studies that used NGS too [3][4][5][6] . We analyzed the Sanger sequences provided in Supplementary Fig.…”