In this study, we identified that endothelial unfolded protein response (UPR) regulates leukemia-induced vascular niche remodeling and contributes to leukemia progression and suppression of hematopoiesis through the involvement of endothelial protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 (eIF2), activating transcription factor 4 (ATF4), and Jagged canonical Notch ligand 1 (JAG1). The gene discussed is EIF2AK3; the disease is leukemia.