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Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia.
Conn, Vanessa M; Gabryelska, Marta; Toubia, John; Kirk, Kirsty; Gantley, Laura; Powell, Jason A; Cildir, Gökhan; Marri, Shashikanth; Liu, Ryan; Stringer, Brett W; Townley, Scott; Webb, Stuart T; Lin, He; Samaraweera, Saumya E; Bailey, Sheree; Moore, Andrew S; Maybury, Mellissa; Liu, Dawei; Colella, Alex D; Chataway, Timothy; Wallington-Gates, Craig T; Walters, Lucie; Sibbons, Jane; Selth, Luke A; Tergaonkar, Vinay; D'Andrea, Richard J; Pitson, Stuart M; Goodall, Gregory J; Conn, Simon J.
Afiliação
  • 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.
  • Gabryelska M; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • 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.
  • Kirk K; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Gantley L; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • 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.
  • Cildir G; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.
  • Marri S; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Liu R; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Stringer BW; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Townley S; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Webb ST; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Lin H; Flinders Health and Medical Research Institute, College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia.
  • Samaraweera SE; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.
  • Bailey S; Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
  • 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.
  • Maybury M; Child Health Research Centre, the University of Queensland, Brisbane, QLD 4101, Australia.
  • Liu D; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.
  • 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.
  • 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.
  • 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 Me
  • Walters L; Adelaide Rural Clinical School, Faculty of Health and Medical Sciences, the University of Adelaide, Adelaide, SA 5000, Australia.
  • Sibbons J; Adelaide Microscopy, Division of Research and Innovation, University of Adelaide, Adelaide, SA 5000, Australia.
  • 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.
  • 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.
  • D'Andrea RJ; Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA 5000, Australia.
  • 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.
  • 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.
  • 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.
Cancer Cell ; 41(7): 1309-1326.e10, 2023 07 10.
Article em En | MEDLINE | ID: mdl-37295428
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 circRNADNA 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Translocação Genética / Leucemia Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Translocação Genética / Leucemia Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália