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

Vanessa M Conn, Marta Gabryelska, John Toubia, Kirsty Kirk, Laura Gantley, Jason A. Powell, Gokhan Cildir, Shashikanth Marri, Ryan Liu, Brett Stringer, Scott Townley, Stuart T. Webb, He Lin, Saumya E Samaraweera, Sheree Bailey, Andrew S. Moore, Mellissa Maybury, Dawei Liu, Alex Colella, Tim ChatawayCraig Wallington-Gates, Lucie Walters, Jane Sibbons, Luke A Selth, Vinay Tergaonkar, Richard D'Andrea, Stuart M. Pitson, Gregory Goodall, Simon J. Conn

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)1309-1326.e10
Number of pages18
JournalCANCER CELL
Volume41
Issue number7
Early online date8 Jul 2023
DOIs
Publication statusPublished - 10 Jul 2023

Keywords

  • acute myeloid leukemia
  • chromosomal translocations
  • circular RNAs
  • genome instability
  • leukemia
  • MLL fusions
  • proteasome
  • R-loops
  • RNA interactome
  • RNA splicing

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