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The ARHGEF2::JAK2 fusion gene combines hyperactive kinase signaling with cytoskeletal regulation, but its functional role in leukemia remains unclear. This study aimed to characterize the oncogenic mechanisms of ARHGEF2::JAK2 and identify key downstream targets. Ba\/F3 cells transduced with ARHGEF2::JAK2 and mouse xenograft models were used to assess proliferation, apoptosis, and leukemogenic potential. RNA sequencing, qPCR, and Western blotting were used to analyze downstream targets, followed by functional validation via shRNA knockdown. Results showed that ARHGEF2::JAK2 conferred cytokine\u2010independent growth, suppressed apoptosis, and drove aggressive leukemia in mice. Ruxolitinib ameliorates ARHGEF2::JAK2\u2010induced leukemogenesis in\u00a0vivo. Transcriptomic analysis identified CCNB1 as a critical downstream effector, and its knockdown reversed the oncogenic effects of ARHGEF2::JAK2, improving survival and reducing organ infiltration. These findings demonstrate that ARHGEF2::JAK2 promotes leukemogenesis via CCNB1 upregulation, suggesting CCNB1 as a potential therapeutic target. This study provides new insights into fusion\u2010driven leukemia pathogenesis.<\/jats:p>","DOI":"10.1111\/ejh.70261","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T14:18:31Z","timestamp":1783088311000},"page":"1238-1248","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ARHGEF2<\/scp>\n                    ::\n                    <scp>JAK2<\/scp>\n                    Fusion Drives Leukemogenesis via\n                    <scp>CCNB1<\/scp>\n                    \u2010Dependent Signaling"],"prefix":"10.1111","volume":"117","author":[{"given":"Yanan","family":"Ma","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology The First Affiliated Hospital of Soochow University  Suzhou China"},{"name":"Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation Soochow 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