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Lookup NU author(s): Dr Sarra RyanORCiD, Dr Lisa RussellORCiD, Professor Anthony MoormanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Extrachromosomal DNA amplification is associated with poor cancer prognoses1. Large numbers of excised signal circles (ESCs) are produced as by-products of antigen receptor rearrangement during V(D)J recombination2,3. However, current dogma states that ESCs are progressively lost through cell division4. Here we show that ESCs replicate and persist through many cell generations and share many properties in common with circular extrachromosomal DNAs. Increased ESC copy numbers at diagnosis of B cell precursor acute lymphoblastic leukaemia were highly correlated with subsequent relapse. By taking advantage of the matching recombination footprint that is formed upon the generation of each ESC, we measured ESC persistence and replication and found increased ESC replication in patients who later relapsed. This increased replication is controlled by cell-intrinsic factors and corresponds to increased expression of DNA replication- and repair-associated genes. Consistent with high ESC levels having a role in disease progression, the number of mutations typical of those caused by the V(D)J recombinase–ESC complex was significantly increased at diagnosis in patients who later relapsed. The number of such mutations in genes associated with relapse increased between diagnosis and relapse, and corresponded to clonal expansion of cells with high ESC copy numbers. These data demonstrate that the by-product of V(D)J recombination, when increased in abundance, potently associates with the V(D)J recombinase to cause adverse disease outcomes.
Author(s): Gao Z, Scott JNF, Edwards MP, Casey D, Wang X, Gillen AD, Ryan S, Russell LJ, Moorman AV, de Tute R, Cargo C, Ford AM, Westhead DR, Boyes J
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2025
Volume: 645
Pages: 774–783
Print publication date: 18/09/2025
Online publication date: 06/08/2025
Acceptance date: 08/07/2025
Date deposited: 19/08/2025
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Research
URL: https://doi.org/10.1038/s41586-025-09372-6
DOI: 10.1038/s41586-025-09372-6
Data Access Statement: Data and code availability statements are available in the paper https://doi.org/10.1038/s41586-025-09372-6
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