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

Rahman, Sunniyat; Bloye, Gianna; Farah, Nadine; Demeulemeester, Jonas; Costa, Joana R; O'Connor, David; Pocock, Rachael; ... Mansour, Marc R; + view all (2024) Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia. BLOOD , 144 (22) pp. 2319-2326. 10.1182/blood.2024024300. Green open access

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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.

Type: Article
Title: Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood.2024024300
Publisher version: https://doi.org/10.1182/blood.2024024300
Language: English
Additional information: For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Keywords: Lymphoid Neoplasia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10204275
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