Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia

Circular RNAs as Trojan horses of leukaemia: A promising path to cancer precision medicine

“…The discovery of circRNAs, such as circMLL(9,10), which are not merely bystanders but active participants in leukaemia, serves as a significant milestone in our comprehension of non‐coding RNAs' roles in cancer. One of the most striking findings in this research is the increased abundance of circMLL(9,10) in paediatric leukaemia compared with controls when quantified from neonatal blood spots (Guthrie cards) 1–7 years prior to disease onset 3 . Furthermore, circMLL(9,10) and circRNAs from other genes, which MLL is known to fuse with, were found to bind to their own DNA locus (forming an R‐loop) corresponding with the MLL breakpoint cluster regions found in patients.…”

A circular RNA-gawky-chromatin regulatory axis modulates stress-induced transcription

“…Recent studies have revealed that a subgroup of cis -acting circRNAs are able to directly regulate Pol II activities by generating stable R-loops in proximity to the loci where they are transcribed ( 31 , 33 ). For example, the RNA–DNA hybrid formed by circMLL and the MLL locus can serve as a physical barrier to induce a robust transcriptional pausing, thereby blocking or slowing down the steps of Pol II elongation in the vicinity of the R-loop sites ( 33 ).…”

“…DRIPc was conducted as previously described ( 33 , 39 , 40 ), with some modifications, and used to investigate the potential of R-loop formation by MRE circRNAs. Cells were incubated with 1.6 ml of TE buffer (10 mM Tris pH 8 and 1 mM EDTA) containing 50 μl of 20% (w/v) SDS and 0.1 μg of proteinase K (Beyotime, ST532) at 37°C overnight.…”

Nuclear circRNA: Impairing genome stability via circR loops

“…To our excites, Conn and the colleagues recently have demonstrated four effects caused by circR loops jointly leading to oncogenic translocations and consequently driving leukemia. 6 The four effects include: (1) pausing RNA polymerase II (RNA Pol II); (2) promoting DNA double-stranded breaks (DSBs); (3) altering chromosome organization; and (4) inhibiting the proteasome. Inhibiting the proteasome, which is known to be needed for stabilizing RNA Pol II 7 and repairing DSBs, 8 may account for the dysfunction of RNA Pol II and increase in DSBs.…”

“…This study by Conn et al has provided lines of convincible evidence for circRNAs to be genetic risks of tumorigenesis by forming circR loops and impairing genome stability. 6 Detecting circRNAs in the neonatal blood spots is a notable highlight, since it was found that circMLL (9,10) significantly increased before the onset of leukemia symptoms, suggesting circRNAs as endogenous RNA carcinogens. Therefore, these circRNAs can be potential candidates as preventive and diagnostic targets.…”