Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia.

Lingyi Wang, Marc R Mansour, Mark A Dawson, Michelle A Kelliher, James O J Davies, Jim R Hughes, Suzana Hadjur, Małgorzata Dawidowska, Roman Jaksik, Juliette Roels, Adele K Fielding, SooWah Lee, David O'Connor, Adam Turna, Tanya Rapoz-D'Silva, Rachael Pocock, Joana R Costa, Nadine Farah, Gianna Bloye, Sunniyat Rahman, Alejandro Gutierrez, Pieter Van Vlierberghe, Peter Van Loo, Jonas Demeulemeester

Journal: Blood 2024;144(22):2319-2326

PMID: 39316719

Abstract

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF-bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that "promoter tethering" of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Address: Department of Haematology, University College London Cancer Institute, London, United Kingdom.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.; Department of Haematology, University College London Cancer Institute, London, United Kingdom.; VIB-KU Leuven Centre for Cancer Biology, Leuven, Belgium.; Department of Developmental Biology and Cancer, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.; Department of Experimental Medicine and Biomedicine, Hull York Medical School, University of York, York, United Kingdom.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Department of Systems Biology and Engineering and Biotechnology Centre, Silesian University of Technology, Gliwice, Poland.; Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.; Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine Centre for Computational Biology, University of Oxford, Oxford, United Kingdom.; Department of Pediatric Oncology, Dana-Farber/Harvard Cancer Center, Boston, MA.; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.; Department of Haematology, University College London Cancer Institute, London, United Kingdom.; Department of Developmental Biology and Cancer, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
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