Modulating retinoid-X-receptor alpha (RXRA) expression sensitizes chronic myeloid leukemia cells to imatinib in vitro...

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Nuclear hormone receptors (NHRs) are largely unstudied in hematological malignancies, with limited exceptions like retinoic acid receptor alpha (RARA).
• Chronic myeloid leukemia (CML) treatment resistance remains a significant clinical challenge.
• Investigating novel therapeutic targets within NHRs could uncover new CML treatment strategies.

Purpose of the Study:

• To profile NHR expression in CML cell lines and identify differential patterns between imatinib-sensitive and resistant phenotypes.
• To evaluate the therapeutic potential of targeting Retinoid-X-receptor alpha (RXRA) in CML.
• To assess the efficacy of combining RXRA ligands with imatinib mesylate (IM) in CML models.

Main Methods:

• Profiling of NHRs and coregulators in CML cell lines and primary CD34+ cells.
• In vitro and in vivo studies using RXRA ligands, RXRA overexpression, and IM in CML models.
• Assessment of cell viability, proliferation, colony formation, leukemic burden, survival, and molecular signaling pathways (BCR::ABL1 kinase, apoptosis, oxidative capacity).

Main Results:

• RXRA was significantly downregulated in IM-resistant CML cell lines and primary CML cells.
• Pre-treatment with RXRA ligands or RXRA overexpression enhanced IM sensitivity, reduced viability, and inhibited proliferation in vitro.
• Combination therapy and RXRA overexpression reduced leukemic burden, improved survival in vivo, decreased BCR::ABL1 signaling, promoted apoptosis, and disrupted cellular oxidative capacity.

Conclusions:

• RXRA downregulation is associated with IM resistance in CML.
• Combining IM with clinically available RXRA ligands demonstrates significant therapeutic potential in CML.
• This combination strategy warrants further investigation for CML patients with suboptimal IM response.