Modulating retinoid-X-receptor alpha (RXRA) expression sensitizes chronic myeloid leukemia cells to imatinib in vitro and reduces disease burden in vivo

  • Front Pharmacol. 2023 May 31:14:1187066. doi: 10.3389/fphar.2023.1187066.
Bharathi M Rajamani  1  2 ,  Raveen Stephen Stallon Illangeswaran  1  2 ,  Esther Sathya Bama Benjamin  1  3 ,  Balaji Balakrishnan  1  4 ,  Daniel Zechariah Paul Jebanesan  1  5 ,  Saswati Das  1  2 ,  Aswin Anand Pai  1  3 ,  Rakhi Thalayattu Vidhyadharan  1 ,  Ajith Mohan  1 ,  Sreeja Karathedath  1 ,  Aby Abraham  1 ,  Vikram Mathews  1 ,  Shaji R Velayudhan  1  6 ,  Poonkuzhali Balasubramanian  1
Affiliations
  • 1. Department of Haematology, Christian Medical College, Vellore, India.
  • 2. Department of Biotechnology, Thiruvalluvar University, Vellore, India.
  • 3. Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India.
  • 4. Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India.
  • 5. Manipal Academy of Higher Education, Manipal, India.
  • 6. Centre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, India.
PMID: 37324449 DOI: 10.3389/fphar.2023.1187066
Abstract

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 IM in-vitro in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34+ cells in-vitro. In-vivo, this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of RXRA inhibited proliferation and improved sensitivity to IM in-vitro. In-vivo, RXRA OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both RXRA OE 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. Conclusion: Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.

Keywords
RXRA; RXRA ligands; chronic myeloid leukemia (CML); imatinib; resistance.