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

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

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.

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