The impact of scaRNA12 deregulation on p53-mediated cellular stress response in B-cell precursor acute lymphoblastic leukaemia

Abstract

Small nucleolar ribonucleic acids (snoRNAs) are a class of small non-coding RNAs involved in the post-transcriptional modification of ribosomal RNAs (rRNA) and small nuclear RNAs (snRNA). Mounting evidence indicates that specific snoRNAs are drivers of oncogenesis, but their role in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is unknown. We found that a small subset of 30 snoRNAs is commonly deregulated in BCP-ALL. Small Cajal body-specific RNA 12 (scaRNA12) was the strongest downregulated snoRNAs in BCP-ALL. Forced expression of scaRNA12 in BCP-ALL cells largely recovered the level of uridine-46 pseudouridylation of U5 snRNA (U5:Ψ46), an important RNA modification for proper splicing and gene expression regulation. We found that scaRNA12 controls a set of genes that belong to pathways that are frequently affected in BCP-ALL samples. We show that scaRNA12 activates p53, which is commonly affected in BCP-ALL even in the absence of p53 mutations. We show that scaRNA12 expression decreased the expression of upstream p53 regulators and provide novel evidence for a role of scaRNA12 in p53 regulation. We found that forced expression of scaRNA12 in BCP-ALL increased p53 activity and significantly enhanced the sensitivity of BCP-ALL to chemotherapeutic reagents. Together, our results suggest a tumour-suppressing role for scaRNA12 in BCP-ALL.