2. Academic Validation
  3. Heterozygous human JAK2V617F activates AhR to drive essential thrombocythemia and promote thrombosis

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

  • J Exp Med. 2025 Dec 1;222(12):e20250153. doi: 10.1084/jem.20250153.
Li Zhou # 1,  Dongxiao Wu # 1,  Yabo Zhou 1,  Dianheng Wang 1,  Zhuo-Yu An 2,  Peng Zhao 2,  Shaoyang Lai 3,  Zhenfeng Wang 1,  Nannan Zhou 1,  Jie Chen 1,  Jiadi Lv 1,  Xiaohui Zhang 2,  Bo Huang 1 4
Affiliations

Affiliations

  • 1 Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.
  • 2 Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation , Beijing, China.
  • 3 The Department of Obstetrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 4 Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • # Contributed equally.
PMID: 41091148 DOI: 10.1084/jem.20250153
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.

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