ARHGAP45 (also known as HMHA1) is a Rho GTPase-activating protein with dual roles in hematopoietic malignancy and vascular biology. Functionally, it acts as a RacGAP that negatively regulates endothelial barrier integrity by inactivating Rac GTPases 1. Silencing ARHGAP45 enhances endothelial barrier function, increases cell migration, and promotes sprout formation 1. In hematopoietics, ARHGAP45 emerged as a shared dependency across blood cancers while remaining dispensable in normal hematopoiesis 2. Under hypoxia, HIF-1α induces ARHGAP45 expression, promoting cancer cell invasion through ROS-dependent mechanisms post-irradiation 3. Clinically, ARHGAP45 carries immunogenic significance as a minor histocompatibility antigen (mHag HA-1), presented via MHC class I, capable of eliciting donor cytotoxic T-lymphocyte responses against hematopoietic malignancies. This dual functionality enables therapeutic exploitation: CAR-T cells targeting ARHGAP45-encoded antigens can specifically eliminate malignant cells, potentially augmented by pharmacologic CDC42 inhibition 2. Genetically, ARHGAP45 variants associate with CD34+ hematopoietic stem cell mobilization levels 45, suggesting roles in stem cell trafficking. These findings position ARHGAP45 as both an oncogenic dependency and immunotherapeutic target in blood malignancies.