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; Gökhan Cildir; Shashikanth Marri; Ryan Liu; Brett W Stringer; Scott Townley; Stuart T Webb; He Lin; Saumya E Samaraweera; Sheree Bailey; Andrew S Moore; Mellissa Maybury; Dawei Liu; Alex D Colella; Timothy Chataway; Craig T Wallington-Gates; Lucie Walters; Jane Sibbons; Luke A Selth; Vinay Tergaonkar; Richard J D'Andrea; Stuart M Pitson; Gregory J Goodall; Simon J Conn

doi:10.1016/j.ccell.2023.05.002

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

Cancer Cell. 2023 Jul 10;41(7):1309-1326.e10. doi: 10.1016/j.ccell.2023.05.002. Epub 2023 Jun 8.

Authors

Vanessa M Conn¹, Marta Gabryelska², John Toubia³, Kirsty Kirk², Laura Gantley², Jason A Powell⁴, Gökhan Cildir⁵, Shashikanth Marri², Ryan Liu², Brett W Stringer², Scott Townley², Stuart T Webb², He Lin², Saumya E Samaraweera⁵, Sheree Bailey⁶, Andrew S Moore⁷, Mellissa Maybury⁸, Dawei Liu⁵, Alex D Colella⁹, Timothy Chataway⁹, Craig T Wallington-Gates¹⁰, Lucie Walters¹¹, Jane Sibbons¹², Luke A Selth¹³, Vinay Tergaonkar¹⁴, Richard J D'Andrea⁵, Stuart M Pitson⁴, Gregory J Goodall⁴, Simon J Conn¹⁵

Affiliations

¹ Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.
² Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
³ Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA 5000, Australia.
⁴ Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, the University of Adelaide, Adelaide, SA 5000, Australia.
⁵ Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.
⁶ Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
⁷ Child Health Research Centre, the University of Queensland, Brisbane, QLD 4101, Australia; Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, QLD 4101, Australia.
⁸ Child Health Research Centre, the University of Queensland, Brisbane, QLD 4101, Australia.
⁹ Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia; Flinders Omics Facility, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
¹⁰ Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, the University of Adelaide, Adelaide, SA 5000, Australia; Flinders Medical Centre, Bedford Park, SA 5042, Australia.
¹¹ Adelaide Rural Clinical School, Faculty of Health and Medical Sciences, the University of Adelaide, Adelaide, SA 5000, Australia.
¹² Adelaide Microscopy, Division of Research and Innovation, University of Adelaide, Adelaide, SA 5000, Australia.
¹³ Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA 5042, Australia.
¹⁴ Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
¹⁵ Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia. Electronic address: simon.conn@flinders.edu.au.

PMID: 37295428
DOI: 10.1016/j.ccell.2023.05.002

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.

Keywords: MLL fusions; R-loops; RNA interactome; RNA splicing; acute myeloid leukemia; chromosomal translocations; circular RNAs; genome instability; leukemia; proteasome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA
Humans
Leukemia* / genetics
Leukemia* / pathology
Mice
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism
Oncogene Proteins, Fusion / genetics
RNA, Circular / genetics
Translocation, Genetic*

Substances

RNA, Circular
Myeloid-Lymphoid Leukemia Protein
DNA
Oncogene Proteins, Fusion