DUX4-rearranged B-ALL: deciphering a biological and clinical conundrum.

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.