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It is an important but not the only determinant of MPN phenotype. We performed high\u2010throughput sequencing on JAK2<\/jats:italic>V617F+<\/jats:sup> essential thrombocythaemia (ET) and polycythaemia vera (PV) patient samples to unveil factors involved in phenotypic heterogeneity and to identify novel therapeutic targets for MPN. Two concurrent mutations that may affect phenotype were identified, including mutations in SH2B3<\/jats:italic>, which is primarily prevalent in PV, and SF3B1<\/jats:italic>, which is more commonly mutated in ET. Next, we conducted transcriptomic analysis at the haematopoietic stem cell (HSC) and megakaryocyte (MK)\u2010erythroid progenitor (MEP) levels. Inflammatory signalling pathways were elevated in both ET HSCs and MEPs, unlike in PV HSCs and MEPs. Notably, Wnt\/\u03b2\u2010catenin signalling was uniquely upregulated during ET haematopoietic differentiation from HSC to MEP, and inhibiting Wnt\/\u03b2\u2010catenin signalling blocked MK differentiation in vitro. Consistently, Wnt\/\u03b2\u2010catenin inhibitor administration decreased platelet counts in JAK2<\/jats:italic>V617F+<\/jats:sup> MPN mice by blocking MEPs and MK progenitors and by inhibiting maturation of MKs, while in wild\u2010type mice, Wnt\/\u03b2\u2010catenin inhibitor did not significantly reduce platelet counts. In conclusion, our findings provide new insights into the mechanisms underlying phenotypic differentiation of JAK2<\/jats:italic>V617F+<\/jats:sup> PV and ET and indicate Wnt\/\u03b2\u2010catenin signalling as a potential therapeutic target for MPN.<\/jats:p>","DOI":"10.1111\/bjh.18669","type":"journal-article","created":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T11:35:09Z","timestamp":1674905709000},"page":"690-703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular analysis of phenotypic heterogeneity inJAK2<\/i>V617F<\/scp>\u2010positive myeloproliferative neoplasms reveals a potential target for therapy"],"prefix":"10.1111","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1604-7666","authenticated-orcid":false,"given":"Wenjing","family":"Gu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood 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