The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (). 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. Retinoid-X-receptor alpha () 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 IM in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34 cells this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of inhibited proliferation and improved sensitivity to IM . OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both and 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. Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.