Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling. Mice with conditional knock-in of Jak2^V617F, the most common molecular driver of MPN, have an increased propensity for NET formation and thrombosis. Inhibition of JAK-STAT signaling with the clinically available JAK2 inhibitor ruxolitinib abrogated NET formation and reduced thrombosis in a deep vein stenosis murine model. We further show that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils and that PAD4 is required for Jak2^V617F-driven NET formation and thrombosis in vivo. Finally, in a population study of more than 10,000 individuals without a known myeloid disorder, JAK2^V617F-positive clonal hematopoiesis was associated with an increased incidence of thrombosis. In aggregate, our results link JAK2^V617F expression to NET formation and thrombosis and suggest that JAK2 inhibition may reduce thrombosis in MPNs through cell-intrinsic effects on neutrophil function.

血栓形成是费城染色体阴性骨髓增殖性肿瘤 (MPN) 的发病率和死亡率的主要原因，这是一种以活化的 Janus 激酶 (JAK) 信号转导和转录激活因子 (STAT) 信号传导为特征的造血克隆性疾病。中性粒细胞胞外陷阱 (NET) 的形成是先天免疫的一个组成部分，与血栓形成有关。我们证明来自 MPN 患者的中性粒细胞为 NET 形成做好了准备，而 JAK 信号的药理学抑制作用减弱了这种作用。有条件敲入Jak2 ^{V617F 的}小鼠MPN 最常见的分子驱动因子 NET 形成和血栓形成的倾向增加。在深静脉狭窄小鼠模型中，使用临床可用的 JAK2 抑制剂鲁索替尼抑制 JAK-STAT 信号可消除 NET 形成并减少血栓形成。我们进一步显示PAD4的表达，对于NET形成所需的蛋白质，在增加JAK2 ^V617F -表达嗜中性粒细胞和PAD4需要的Jak2 ^V617F驱动的NET形成和血栓形成体内。最后，在对 10,000 多名没有已知骨髓疾病的个体进行的人群研究中，JAK2 ^V617F阳性克隆造血与血栓形成的发生率增加有关。总的来说，我们的结果链接JAK2 ^V617F表达对 NET 形成和血栓形成，并表明 JAK2 抑制可能通过对中性粒细胞功能的细胞内在影响来减少 MPN 中的血栓形成。