T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, representing 10–15% of pediatric acute lymphoblastic leukemia (ALL) cases. Despite advances in treatment, the prognosis for relapsed or refractory T-ALL remains poor, with event-free survival rates below 10%. This underscores the need for novel therapeutic approaches.

Retinoid X receptor alpha (RXRα), a nuclear receptor regulating gene expression in differentiation, proliferation, and apoptosis, has been implicated in cancers like acute promyelocytic leukemia (APL). However, its role in T-ALL remains unexplored. Analysis of 264 pediatric and young adult T-ALL samples (Liu et al., 2017) revealed RXRα mRNA upregulation in early T-cell precursor (ETP)-ALL phenotypes and pre-cortical maturation stage groups.

Validation through quantitative PCR (qPCR) and western blotting across seven T-ALL cell lines showed variable RXRα mRNA levels, with significant upregulation in KOPTK1 cells. Western blot confirmed RXRα protein presence across all lines, although transcript and protein levels were not consistently correlated. MTS assays using the RXRα agonist 9-cis-retinoic acid (9-cis-RA) demonstrated reduced leukemic cell viability in six T-ALL lines (KOPTK1, ALL-SIL, KARPAS45, JURKAT, LOUCY, PER117) in a dose-dependent manner. The treatment of the derived IC50 value revealed that 9-cis-RA treatment increased apoptosis.

Combination treatments of 9-cis-retinoic acid (9-cis-RA) with standard and investigational T-ALL chemotherapy drugs demonstrated synergistic effects with Venetoclax, a Bcl-2 inhibitor, in multiple patient-derived T-ALL samples and cell lines, including LOUCY, ALL-SIL, PER117, and KARPAS45. These findings highlight the therapeutic potential of RXRα as a target in T-ALL treatment. Future research will evaluate the preclinical efficacy of additional RXRα agonists in combination with Venetoclax and investigate the underlying mechanisms contributing to the observed synergistic effects in preclinical models.