Long non-coding RNA PCAT18 defines a leukemia-specific regulatory network in pediatric T-ALL.

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of gene expression across various levels, including transcriptional, post-transcriptional, and epigenetic mechanisms. In pediatric T-cell acute lymphoblastic leukemia (T-ALL), dysregulated lncRNA expression contributes to altered cell proliferation, apoptosis resistance, treatment response, and disease progression. Our previous work identified a distinct lncRNA signature capable of differentiating T-ALL from B-ALL, highlighting their diagnostic potential. In our work, we focused on the lncRNA called PCAT18. We used RNA-seq analysis on 13 patients with T-ALL in comparison to cord blood cells. We performed a preliminarly in silico analysis throught WGCNA to reveal interesting co-expression network of target lncRNA. PCAT18 silencing in two T-ALL cell models allowed to investigate its functional role in physiological and pathological states. Finally, RNA-seq analyses of PCAT18 silenced cell line in comparison with control cell line was carried out to identify and confirm pathways significantly altered by its absence. Our network analysis (WGCNA) revealed that PCAT18 is highly connected within a module strongly associated with the T-ALL phenotype. Functional assays in JURKAT cells demonstrated that PCAT18 knockdown paradoxically enhanced proliferation, induced G1 phase accumulation, reduced p27 expression, and upregulated Cyclin B, suggesting disrupted checkpoint control and uncoordinated cell cycle progression. Additionally, deregulation of FOXP3, NOTCH3, HSP90AA1, and HSPA8 implicated PCAT18 in stress response pathways and lineage identity maintenance. These findings support a tumor-suppressive role for PCAT18 in T-ALL, in contrast to its oncogenic role in solid tumors. PCAT18 appears to operate at the intersection of transcriptional regulation, cell cycle control, and stress adaptation. Its disease- and lineage-specific expression makes it a promising candidate for biomarker development and therapeutic targeting in pediatric T-ALL. This study expands our understanding of lncRNA biology in leukemia and uncovers novel regulatory mechanisms in T-ALL pathogenesis.