Introduction:The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (RARA).Methods:Here we profiled the expression of various NHRs and their coregulators in Chronic myeloid leukemia (CML) cell lines and identified a significant differential expression pattern between inherently imatinib mesylate (IM)-sensitive and resistant cell lines.Results:Retinoid-X-receptor alpha (RXRA) was downregulated in CML cell lines inherently resistant to IM and in primary CML CD34+cells. Pre-treatment with clinically relevant RXRA ligands improved sensitivity to IMin-vitroin both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34+cellsin-vitro. In-vivo,this combination reduced leukemic burden and prolonged survival. Overexpression (OE) ofRXRAinhibited proliferation and improved sensitivity to IMin-vitro.In-vivo, RXRAOE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. BothRXRA OEand ligand treatment markedly reduced BCR::ABL1 downstream kinase activation, activating apoptotic cascades and improving sensitivity to IM. Importantly, RXRA OE also led to the disruption of the oxidative capacity of these cells.Conclusion:Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.