Nadeu Ferran, Shuai Shimin, Clot Guillem, Hilton Laura K, Diaz-Navarro Ander, Martín Silvia, Royo Romina, Baumann Tycho, Kulis Marta, López-Oreja Irene, Cossio Manuel, Lu Junyan, Ljungström Viktor, Young Emma, Plevova Karla, Knisbacher Binyamin A, Lin Ziao, Hahn Cynthia K, Bousquets Pablo, Alcoceba Miguel, González Marcos, Colado Enrique, Payer Ángel R, Aymerich Marta, Terol María J, Rivas-Delgado Alfredo, Enjuanes Anna, Ruiz-Gaspà Sílvia, Chatzikonstantinou Thomas, Hägerstrand Daniel, Jylhä Cecilia, Skaftason Aron, Mansouri Larry, Stranska Kamila, Doubek Michael, van Gastel-Mol Ellen J, Davis Zadie, Walewska Renata, Scarfò Lydia, Trentin Livio, Visentin Andrea, Parikh Sameer A, Rabe Kari G, Moia Riccardo, Armand Marine, Rossi Davide, Davi Frederic, Gaidano Gianluca, Kay Neil E, Shanafelt Tait D, Ghia Paolo, Oscier David, Langerak Anton W, Beà Sílvia, López-Guillermo Armando, Neuberg Donna, Wu Catherine J, Getz Gad, Pospisilova Sarka, Stamatopoulos Kostas, Rosenquist Richard, Huber Wolfgang, Zenz Thorsten, Colomer Dolors, Martín-Subero José I, Delgado Julio, Morin Ryan D, Stein Lincoln D, Puente Xose S, Campo Elías
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
Leukemia. 2025 Jun 30. doi: 10.1038/s41375-025-02667-7.
Recurrent mutations in the third base of U1 spliceosomal RNA responsible for marked splicing and expression abnormalities have been described in chronic lymphocytic leukemia (CLL) and some solid tumors. However, the clinical significance of these mutations in large and independent CLL cohorts as well as their presence in other B-cell neoplasms is unknown. Here we characterized U1 mutations in 1670 CLL and 363 mature B-cell lymphomas. We confirmed that the g.3A>C U1 mutation is found in 3.5% of CLL, which conferred rapid disease progression independently of the main biological and clinical prognostic markers of the disease. Additionally, a recurrent g.9C>T mutation was found in 1.5% of CLL causing downstream splicing alterations and associated with adverse prognosis. We also identified a g.4C>T mutation in 10% of diffuse large B-cell lymphomas of the germinal center subtype and a g.7A>G mutation in 30% of EBV-negative Burkitt lymphomas, both of which altered the splicing pattern of multiple genes. This study reveals novel, recurrent, and tumor-specific U1 mutations in mature B-cell neoplasms with biological and prognostic implications, thus establishing U1 as a novel pan-B-cell malignancy driver gene.
慢性淋巴细胞白血病（CLL）和一些实体瘤中已发现负责显著剪接和表达异常的U1剪接体RNA第三个碱基的复发性突变。然而，这些突变在大型独立CLL队列中的临床意义以及它们在其他B细胞肿瘤中的存在情况尚不清楚。在此，我们对1670例CLL和363例成熟B细胞淋巴瘤中的U1突变进行了特征分析。我们证实，3.5%的CLL中存在g.3A>C U1突变，该突变独立于疾病的主要生物学和临床预后标志物导致疾病快速进展。此外，1.5%的CLL中发现了复发性g.9C>T突变，导致下游剪接改变并与不良预后相关。我们还在10%的生发中心亚型弥漫性大B细胞淋巴瘤中鉴定出g.4C>T突变，在30%的EBV阴性伯基特淋巴瘤中鉴定出g.7A>G突变，这两种突变均改变了多个基因的剪接模式。这项研究揭示了成熟B细胞肿瘤中具有生物学和预后意义的新型、复发性和肿瘤特异性U1突变，从而确立U1为一种新型的泛B细胞恶性肿瘤驱动基因。
