Functional relevance of circRNA aberrant expression in pediatric acute leukemia with MLL/AF4 fusion

Acute lymphoblastic leukemia (ALL) is the most common malignancy observed in pediatric patients and the MLL-AF4 rearranged is the most frequent and most aggressive subtype of BCP-ALL observed in infant patients that usually shows poor prognosis. Despite many efforts to identify molecular mechanisms sustaining leukemogenesis and to recapitulate disease pathogenesis in models, this subtype of leukemia remains aggressive and difficult to comprehend. The emerging world of circRNAs was never taken into account for this hostile leukemia subtype. CircRNAs are covalently closed RNA molecules produced by a process called backsplicing that gives rise to molecules with unique backsplicing sites, sequences not present in normal transcripts, already described to have different functions and involved in many pathological pathways. In this study, we described for the first time the circRNA landscape of MLL-AF4 BCP-ALL translocated infant patients. Moreover, by high-impact screening, designing siRNA molecules targeting the backsplicing site of deregulated and prioritized molecules, we identified putative oncogenic roles for four circRNAs in MLL-AF4 cell lines. Interestingly, by bioinformatic predictions of circRNAs’ functions we identified putative regulatory axes related to the MLL-AF4 chimera hypothesizing a co-occurring mechanism in the leukemogenesis process between circRNAs and the fusion transcript.