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

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 circRNA:DNA hybrids (circR loops) at their cognate loci. These circR loops pro-mote transcriptional pausing, proteasome inhibition, chromatin re-organization, and DNA breakage. Impor-tantly, 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 chromo-somal translocations by endogenous RNA carcinogens in leukemia.

Automated summary

The first step of oncogenesis is the acquisition of genetic mutations to initiate and sustain malignancy. In acute leukemias, the formation of a potent oncogene called the MLL recombinome by chromosomal translocations is a key example of this initiation phase. Circular RNAs (circRNAs), a type of covalently closed RNA molecules, are enriched within the MLL recombinome and can bind DNA to form circRNA:DNA hybrids (circR loops) at specific sites. These circR loops promote transcriptional pausing, chromatin re-organization, and DNA breakage, leading to the generation of clinically relevant chromosomal translocations and hastening disease onset in mouse leukemia xenograft models.