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How specific driver mutations affect hematopoietic stem cell (HSC) heterogeneity and their relation to ET pathogenesis remain unclear. Here, by using single\u2010cell RNA sequencing (scRNA\u2010seq) combined with driver mutation detection across ET patients, it is found that\n MPL<\/jats:italic>\n \u2010mutated HSCs exhibited aberrant metabolism,\n CALR<\/jats:italic>\n \u2010mutated HSCs displayed active cell cycling, while\n JAK2<\/jats:italic>\n V617F<\/jats:sup>\n \u2010mutated HSCs demonstrated enhanced megakaryocyte (Mk) priming capacity and interferon (IFN) response. An HSC subset is identified in TN ET that transcriptionally resembled driver\u2010mutated HSCs, exhibiting enhanced megakaryocytic priming and proliferative activity. Notably, the frequency of a CXCR4\n +<\/jats:sup>\n HSC subset is reduced across the ET spectrum. Loss of CXCR4\n +<\/jats:sup>\n HSCs skewed lineage differentiation of HSCs toward the myeloid lineage, whereas restoring this subset delayed the onset of ET. Altogether, this study reveals both the shared and distinct molecular features of mutant HSCs in ET and provides novel insights into the pathogenesis and potential therapeutic strategies of ET.\n <\/jats:p>","DOI":"10.1002\/advs.202505249","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T10:18:07Z","timestamp":1763720287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development"],"prefix":"10.1002","volume":"13","author":[{"given":"Jingyuan","family":"Tong","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood Diseases Haihe Laboratory of Cell Ecosystem Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Tianjin 300020 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