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.

中文翻译：

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编码V140A的复发性ECSIT突变会触发结外NK / T细胞淋巴瘤中的过度炎症并促进噬血细胞综合征。

噬血细胞综合征（HPS）是一种致命的高炎症性疾病，其机制尚不明确，最常发生在结外自然杀伤/ T细胞淋巴瘤（ENKTL）中。通过ENKTL肿瘤正常样品的外显子组测序，我们在Toll途径（ECSIT）基因的进化保守信号中间物（编码ECSIT的V140A变体）中鉴定出一个热点突变（c.419T> C）。由于ECSIT-V140A对S100A8和S100A9异二聚体的亲和力增加，因此它能比野生型蛋白更有效地激活NF-κB，从而促进NADPH氧化酶活性。响应LPS，ECSIT-T419C敲入小鼠的腹膜NADPH氧化酶活性高于野生型ECSIT小鼠。ECSIT-T419C转染的ENKTL细胞系产生了肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ，在细胞培养和小鼠异种移植物中诱导巨噬细胞活化和大量细胞因子分泌。在患有ENKTL的患者中，ECSIT-V140A与NF-κB活化，HPS发生率升高和预后不良有关。免疫抑制药物沙利度胺可阻止NF-κB与其靶基因（包括TNF和IFNG）的启动子结合，沙利度胺和地塞米松的联合治疗可延长植入ECSIT-T419C转染的ENKTL细胞的小鼠的存活率。对于两名表达ECSIT-V140A的HPS患者，我们在常规的含地塞米松治疗方案中添加了沙利度胺，并且观察到其HPS逆转和无病生存时间超过3年。这些发现为ENKTL相关的HPS提供了机械方面的见识和潜在的治疗策略。