Heterozygous human JAK2V617F activates AhR to drive essential thrombocythemia and promote thrombosis.

IF 10.6 1区医学 Q1 IMMUNOLOGY

Journal of Experimental Medicine Pub Date : 2025-12-01 Epub Date: 2025-10-15 DOI:10.1084/jem.20250153

Li Zhou, Dongxiao Wu, Yabo Zhou, Dianheng Wang, Zhuo-Yu An, Peng Zhao, Shaoyang Lai, Zhenfeng Wang, Nannan Zhou, Jie Chen, Jiadi Lv, Xiaohui Zhang, Bo Huang

{"title":"Heterozygous human JAK2V617F activates AhR to drive essential thrombocythemia and promote thrombosis.","authors":"Li Zhou, Dongxiao Wu, Yabo Zhou, Dianheng Wang, Zhuo-Yu An, Peng Zhao, Shaoyang Lai, Zhenfeng Wang, Nannan Zhou, Jie Chen, Jiadi Lv, Xiaohui Zhang, Bo Huang","doi":"10.1084/jem.20250153","DOIUrl":null,"url":null,"abstract":"<p><p>JAK2V617F causes >50% essential thrombocythemia (ET) and >90% polycythemia vera (PV). How such a single mutation causes distinct disorders remains a long-standing enigma. Here, we show that heterozygous JAK2V617F activates the transcription factor aryl hydrocarbon receptor (AhR), which biases MEP differentiation toward megakaryocytes in ET patients. In contrast, most PV patients' JAK2V617F exhibits a homozygous mutation that does not activate AhR. We found that JAK2V617F forms a heterodimer with JAK2 to recruit and activate STAT1, thereby inducing AhR activation and driving ET pathogenesis. However, JAK2 forms V617F homodimers in PV patients, which activate STAT5 and drive PV development. In addition to increasing platelet number, activated AhR may enhance platelet activity via the COX2-TXA2 axis. Importantly, targeting AhR inhibits thrombocytosis in JAK2V617F ET humanized mice. These findings not only elucidate the molecular mechanism of JAK2V617F ET but also provide a potential strategy for its treatment.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1084/jem.20250153","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/10/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

JAK2V617F causes >50% essential thrombocythemia (ET) and >90% polycythemia vera (PV). How such a single mutation causes distinct disorders remains a long-standing enigma. Here, we show that heterozygous JAK2V617F activates the transcription factor aryl hydrocarbon receptor (AhR), which biases MEP differentiation toward megakaryocytes in ET patients. In contrast, most PV patients' JAK2V617F exhibits a homozygous mutation that does not activate AhR. We found that JAK2V617F forms a heterodimer with JAK2 to recruit and activate STAT1, thereby inducing AhR activation and driving ET pathogenesis. However, JAK2 forms V617F homodimers in PV patients, which activate STAT5 and drive PV development. In addition to increasing platelet number, activated AhR may enhance platelet activity via the COX2-TXA2 axis. Importantly, targeting AhR inhibits thrombocytosis in JAK2V617F ET humanized mice. These findings not only elucidate the molecular mechanism of JAK2V617F ET but also provide a potential strategy for its treatment.

查看原文本刊更多论文

杂合子人JAK2V617F激活AhR驱动必需的血小板增多症，促进血栓形成。

JAK2V617F引起>50%的原发性血小板增多症（ET）和>90%的真性红细胞增多症（PV）。如此单一的突变如何导致不同的疾病仍然是一个长期存在的谜。在这里，我们发现杂合子JAK2V617F激活转录因子芳烃受体（AhR），使ET患者MEP向巨核细胞分化。相比之下，大多数PV患者的JAK2V617F表现出不激活AhR的纯合突变。我们发现JAK2V617F与JAK2形成异源二聚体募集并激活STAT1，从而诱导AhR激活并驱动ET发病机制。然而，JAK2在PV患者中形成V617F同型二聚体，激活STAT5并驱动PV的发展。除了增加血小板数量外，活化的AhR可能通过cox - txa2轴增强血小板活性。重要的是，靶向AhR抑制JAK2V617F ET人源化小鼠的血小板增多。这些发现不仅阐明了JAK2V617F ET的分子机制，而且为其治疗提供了潜在的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Experimental Medicine 医学-免疫学

CiteScore

26.60

自引率

1.30%

发文量

189

审稿时长

3-8 weeks

期刊介绍： Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.