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https://hdl.handle.net/2440/140220
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Type: | Journal article |
Title: | Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia |
Author: | Conn, V.M. Gabryelska, M. Toubia, J. Kirk, K. Gantley, L. Powell, J.A. Cildir, G. Marri, S. Liu, R. Stringer, B.W. Townley, S. Webb, S.T. Lin, H. Samaraweera, S.E. Bailey, S. Moore, A.S. Maybury, M. Liu, D. Colella, A.D. Chataway, T. et al. |
Citation: | Cancer Cell, 2023; 41(7):1309-1326.e10 |
Publisher: | Cell Press (Elsevier) |
Issue Date: | 2023 |
ISSN: | 1535-6108 1878-3686 |
Statement of Responsibility: | Vanessa M. Conn, Marta Gabryelska, John Toubia, Kirsty Kirk, Laura Gantley, Jason A. Powell, Go, khan 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, and Simon J. Conn |
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: | acute myeloid leukemia chromosomal translocations circular RNAs genome instability leukemia MLL fusions proteasome R-loops RNA interactome RNA splicing |
Description: | Published: June 8, 2023 |
Rights: | © 2023 Elsevier Inc. |
DOI: | 10.1016/j.ccell.2023.05.002 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/GNT1089167 http://purl.org/au-research/grants/nhmrc/GNT1144250 http://purl.org/au-research/grants/nhmrc/GNT1198014 http://purl.org/au-research/grants/arc/FT160100318 |
Published version: | http://dx.doi.org/10.1016/j.ccell.2023.05.002 |
Appears in Collections: | Medicine publications |
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