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

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

Free article

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

Vanessa M Conn et al. Cancer Cell. 2023.

Free article

. 2023 Jul 10;41(7):1309-1326.e10.

doi: 10.1016/j.ccell.2023.05.002. Epub 2023 Jun 8.

Authors

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

CircR-looping the leukemic translocations: The cause of MLL translocations explained.
Chen M. Chen M. Mol Cell. 2023 Jul 6;83(13):2164-2166. doi: 10.1016/j.molcel.2023.05.037. Mol Cell. 2023. PMID: 37419090
The circ du RNA.
Brewer G. Brewer G. Nat Rev Cancer. 2023 Sep;23(9):578. doi: 10.1038/s41568-023-00613-2. Nat Rev Cancer. 2023. PMID: 37558902 No abstract available.
The dark side of circular RNA, a new driver of genome instability.
Sharma AK, Thomas A. Sharma AK, et al. Cell Chem Biol. 2023 Aug 17;30(8):861-863. doi: 10.1016/j.chembiol.2023.07.013. Cell Chem Biol. 2023. PMID: 37595549

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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