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 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. [Display omitted] •CircRNA:DNA interactions found genome wide, concentrating within the MLL recombinome•CircMLL(9,10) abundant in infant leukemia and binds MLL breakpoint cluster region•CircMLL(9,10) inhibits proteasome to promote DNA breaks and chromosomal translocations•CircRNAs can be endogenous RNA carcinogens driving leukemogenic oncogenes Conn et al. identify circular RNA:DNA interactions concentrated within the MLL recombinome, commonly translocated in acute myeloid leukemia. Both in vitro and in vivo experiments demonstrate that endogenous circular RNAs inhibit the proteasome, promote DNA double-stranded breaks, reorganize chromatin, and promote oncogenic gene translocations which drive leukemia.