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Lookup NU author(s): Dr Jack Bakewell, Professor Anthony MoormanORCiD, Sarra Ryan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. The DUX4 gene, located within repetitive subtelomeric arrays on chromosomes 4 and 10, plays a critical role in early embryogenesis and has been implicated in several human diseases, including facioscapulohumeral muscular dystrophy (FSHD) and cancer. In B-cell acute lymphoblastic leukemia (B-ALL), DUX4 rearrangements (DUX4-r) define a distinct genomic subtype affecting 5–10% of cases, which is more frequent among older children and teenagers. These rearrangements produce truncated DUX4 proteins with neomorphic transcriptional activity, resulting in aberrant gene expression programs and alternative splicing that disrupt normal B-cell precursor development. Patients with DUX4-r B-ALL often present with poor initial treatment responses, though they typically achieve excellent long-term survival rates with intensive chemotherapy regimens. The cryptic nature of DUX4 rearrangements has historically posed significant challenges to accurate detection, but recent advancements in next-generation sequencing technologies, including RNA and long-read sequencing, and improved immunophenotyping strategies—such as the use of CD371 as a surrogate marker—are enhancing diagnostic accuracy. This review explores the genetic and biological features of DUX4 and its rearrangements, shedding light on their role in leukemogenesis and associated clinical outcomes. Additionally, we highlight emerging technologies that enable the detection of DUX4-r and discuss their implications for clinical use and research. An improved understanding of DUX4 biology and its oncogenic potential may pave the way for novel treatment strategies, ultimately improving outcomes for patients with DUX4-r B-ALL.
Author(s): Bakewell J, Moorman AV, Ryan SL
Publication type: Review
Publication status: Published
Journal: Leukemia
Year: 2025
Pages: Epub ahead of print
Online publication date: 12/09/2025
Acceptance date: 01/09/2025
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41375-025-02758-5
DOI: 10.1038/s41375-025-02758-5
PubMed id: 40940582
Data Access Statement: Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
