CircRNAome of childhood B-ALL: Deciphering subtype-specific expression profiles and functional involvement

Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising 6 genetic subtypes and 7 B-cell controls from two independent cohorts, we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis, 110 overexpressed and 134 underexpressed circRNAs were identified consistently for each subtype in both cohorts. Focusing on overexpressed circRNAs, most of them had a subtype-specific expression, with 73 circRNA (66%) only expressed in one subgroup. Interestingly, TCF3/PBX1 subtype was the one with the highest number of unique circRNAs, as well as overexpressed circRNAs. Our results indicated that NUDT21, an RNA-binding protein (RBP) involved in circRNA biogenesis, contributes to this circRNA enrichment in TCF3-PBX1 ALL. Further functional characterization using CRISPR-Cas13d system demonstrated that circBARD1 (hsa_circ_0001098), overexpressed in TCF3/PBX1 subtype, was involved in cancer phenotypes. Our results suggest that circRNAs could have a role in the pathogenesis of childhood B-ALL, adding a new layer of complexity in leukemogenesis. Profiling the circRNAome of pediatric B cell acute lymphoblastic leukemia patients