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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\u2019 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\u2013TXA2 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.<\/jats:p>","DOI":"10.1084\/jem.20250153","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T06:20:48Z","timestamp":1757139648000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Heterozygous human JAK2V617F activates AhR to drive essential thrombocythemia and promote thrombosis"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6211-1860","authenticated-orcid":true,"given":"Li","family":"Zhou","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College 1 Department of Immunology & State Key Laboratory of Common Mechanism Research for 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