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

Autor:	Rahman S; University College London, London, United Kingdom., Bloye G; University College London, London, United Kingdom., Farah N; University College London, London, United Kingdom., Demeulemeester J; VIB - KU Leuven, Leuven, Belgium., Costa JR; University College London, London, United Kingdom., O'Connor D; University College London, London, United Kingdom., Pocock R; University College London, London, United Kingdom., Rapoz-D'Silva T; University College London, London, United Kingdom., Turna A; Lister Hospital, Stevenage, United Kingdom., Wang L, Lee SW; University College London, London, United Kingdom., Fielding AK; UCL Cancer Institute, London, United Kingdom., Roels J; Genentech, South San Francisco, California, United States., Jaksik R; Silesian University of Technology, Gliwice, Poland., Dawidowska M; Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland., Van Vlierberghe P; Ghent University, Ghent, Belgium., Hadjur S; University College London, London, United Kingdom., Hughes JR; Oxford University, Oxford, United Kingdom., Davies J; University of Oxford, Oxford, United Kingdom., Gutierrez A; St. Jude Children's Research Hospital, Memphis, Tennessee, United States., Kelliher M; UMass Chan Medical School, Worcester, Massachusetts, United States., Van Loo P; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Dawson MA; Peter MacCallum Cancer Centre, Melbourne, Australia., Mansour MR; University College London, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Sep 24. Date of Electronic Publication: 2024 Sep 24.
DOI:	10.1182/blood.2024024300
Abstrakt:	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. (Copyright © 2024 American Society of Hematology.)
Databáze:	MEDLINE
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