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

Animals Mice Humans Translocation, Genetic RNA, Circular / genetics Myeloid-Lymphoid Leukemia Protein / genetics Leukemia / genetics DNA Oncogene Proteins, Fusion / genetics
MLL fusions R-loops RNA interactome RNA splicing acute myeloid leukemia chromosomal translocations circular RNAs genome instability leukemia proteasome

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
10 07 2023
Historique:
received: 11 01 2023
revised: 03 03 2023
accepted: 03 05 2023
medline: 13 7 2023
pubmed: 10 6 2023
entrez: 9 6 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2023.05.002 PMID: 37295428
pubmed: 37295428
pii: S1535-6108(23)00169-1
doi: 10.1016/j.ccell.2023.05.002
pii:
doi:

Substances chimiques

RNA, Circular 0
Myeloid-Lymphoid Leukemia Protein 149025-06-9
DNA 9007-49-2
Oncogene Proteins, Fusion 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1309-1326.e10

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Vanessa M Conn (VM)

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.

Marta Gabryelska (M)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

John Toubia (J)

Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA 5000, Australia.

Kirsty Kirk (K)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Laura Gantley (L)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Jason A Powell (JA)

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.

Gökhan Cildir (G)

Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.

Shashikanth Marri (S)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Ryan Liu (R)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Brett W Stringer (BW)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Scott Townley (S)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Stuart T Webb (ST)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

He Lin (H)

Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.

Saumya E Samaraweera (SE)

Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.

Sheree Bailey (S)

Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.

Andrew S Moore (AS)

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.

Mellissa Maybury (M)

Child Health Research Centre, the University of Queensland, Brisbane, QLD 4101, Australia.

Dawei Liu (D)

Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.

Alex D Colella (AD)

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.

Timothy Chataway (T)

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.

Craig T Wallington-Gates (CT)

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.

Lucie Walters (L)

Adelaide Rural Clinical School, Faculty of Health and Medical Sciences, the University of Adelaide, Adelaide, SA 5000, Australia.

Jane Sibbons (J)

Adelaide Microscopy, Division of Research and Innovation, University of Adelaide, Adelaide, SA 5000, Australia.

Luke A Selth (LA)

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.

Vinay Tergaonkar (V)

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.

Richard J D'Andrea (RJ)

Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.

Stuart M Pitson (SM)

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.

Gregory J Goodall (GJ)

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.

Simon J Conn (SJ)

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.

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Classifications MeSH

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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Circular RNAs drive oncogenic chromosomal...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Translocation génétique › Circular RNAs drive oncogenic chromosomal...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN circulaire › Circular RNAs drive oncogenic chromosomal...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéine de la leucémie myéloïde-lymphoïde › Circular RNAs drive oncogenic chromosomal...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › Circular RNAs drive oncogenic chromosomal...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › Circular RNAs drive oncogenic chromosomal...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › Circular RNAs drive oncogenic chromosomal...