Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia.
Cancer Cell
; 41(7): 1309-1326.e10, 2023 07 10.
Article
in En
| MEDLINE
| ID: mdl-37295428
ABSTRACT
The first step of oncogenesis is the acquisition of a repertoire of genetic mutations to initiate and sustain the malignancy. An important example of this initiation phase in acute leukemias is the formation of a potent oncogene by chromosomal translocations between the mixed lineage leukemia (MLL) gene and one of 100 translocation partners, known as the MLL recombinome. Here, we show that circular RNAs (circRNAs)-a family of covalently closed, alternatively spliced RNA molecules-are enriched within the MLL recombinome and can bind DNA, forming circRNADNA hybrids (circR loops) at their cognate loci. These circR loops promote transcriptional pausing, proteasome inhibition, chromatin re-organization, and DNA breakage. Importantly, overexpressing circRNAs in mouse leukemia xenograft models results in co-localization of genomic loci, de novo generation of clinically relevant chromosomal translocations mimicking the MLL recombinome, and hastening of disease onset. Our findings provide fundamental insight into the acquisition of chromosomal translocations by endogenous RNA carcinogens in leukemia.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Translocation, Genetic
/
Leukemia
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Cell
Journal subject:
NEOPLASIAS
Year:
2023
Document type:
Article
Affiliation country:
Australia