Çağla KAYABAŞI, Cumhur GÜNDÜZ
Meandros Medical and Dental Journal - 2026;27(1):17-25
Objective: Leukemia stem cells (LSCs) are central to therapy resistance and disease relapse. Long non-coding RNAs (lncRNAs) are critical epigenetic regulators whose dysregulation sustains leukemic stemness. This study evaluated the capacity of resveratrol to selectively modulate the lncRNA expression landscape in LSCs compared with healthy hematopoietic stem cells (HSCs). Materials and Methods: Human LSC and healthy HSC lines were treated with 16.7 µM resveratrol for 72 hours. Differential expression of 90 lncRNAs was assessed using quantitative real-time PCR. Integrated RNA-protein interaction network and functional enrichment analyses were performed using the RAIN database integrated with the STRING consortium to identify molecular hubs targeted by resveratrol. Results: Resveratrol markedly reprogrammed the LSC transcriptome, resulting in the upregulation of nine and downregulation of nineteen lncRNAs. Notably, the expression of the tumor suppressor anti-NOS2A was restored (5.70-fold), a molecule previously identified as strongly suppressed in LSCs. Significant induction was also observed for PTENP1 (6.15-fold) and LincRNA-SFMBT2 (8.30-fold), while oncogenic lncRNAs HOTTIP (-11.34-fold), SNHG5 (-8.99-fold), and MALAT1 (-7.61-fold) were strongly inhibited. In contrast, healthy HSCs exhibited a substantially attenuated transcriptional response, indicating a more pronounced transcriptional response in LSCs compared with HSCs, although measurable lncRNA alterations were also observed in the healthy cell population. Integrated network analysis further associated upregulated lncRNAs with Jak-STAT signaling and apoptotic regulation (Caspase-3/7), whereas downregulated networks were linked to epigenetic maintenance and cell cycle progression. Conclusion: Resveratrol acts as a selective modulator in LSCs by restoring tumor-suppressive signatures and suppressing oncogenic drivers through lncRNA alterations. These findings support the potential of resveratrol as a complementary strategy to target LSC-mediated resistance while sparing normal hematopoiesis.
