Frontiers in Pharmacology (May 2023)

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

  • Bharathi M. Rajamani,
  • Bharathi M. Rajamani,
  • Raveen Stephen Stallon Illangeswaran,
  • Raveen Stephen Stallon Illangeswaran,
  • Esther Sathya Bama Benjamin,
  • Esther Sathya Bama Benjamin,
  • Balaji Balakrishnan,
  • Balaji Balakrishnan,
  • Daniel Zechariah Paul Jebanesan,
  • Daniel Zechariah Paul Jebanesan,
  • Saswati Das,
  • Saswati Das,
  • Aswin Anand Pai,
  • Aswin Anand Pai,
  • Rakhi Thalayattu Vidhyadharan,
  • Ajith Mohan,
  • Sreeja Karathedath,
  • Aby Abraham,
  • Vikram Mathews,
  • Shaji R. Velayudhan,
  • Shaji R. Velayudhan,
  • Poonkuzhali Balasubramanian

DOI
https://doi.org/10.3389/fphar.2023.1187066
Journal volume & issue
Vol. 14

Abstract

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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.

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