ARHGEF2::JAK2 Fusion Drives Leukemogenesis via CCNB1-Dependent Signaling

Leukemia is a heterogeneous malignancy with poor outcomes in refractory cases, and fusion genes involving JAK2 are known oncogenic drivers. 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-independent growth, suppressed apoptosis, and drove aggressive leukemia in mice. Ruxolitinib ameliorates ARHGEF2::JAK2-induced leukemogenesis in vivo. 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-driven leukemia pathogenesis.