Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms

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.

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Journal
Leukemia
Published
2025-06-30
DOI
https://doi.org/10.1038/s41375-025-02667-7
Citations
1
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
1.63

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article

Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms

Thorsten Zenz, Kamila Stránská, Gad A. Getz, Neil E. Kay et al.
1 citations
Leukemia
Chronic Lymphocytic Leukemia Research
1.63
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Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms

Thorsten Zenz, Kamila Stránská, Gad A. Getz, Neil E. Kay, Donna Neuberg, Renata J. Walewska, Manuel Cossio, Guillem Clot, Romina Royo, Silvia Martín, Sameer Ashok Parikh, Frédéric Davi, Livio Trentin, Laura K. Hilton, Julio Delgado, Davide Rossi, Richard Rosenquist, Ziao Lin, Ander Díaz‐Navarro, José I. Martı́n-Subero, Sílvia Ruiz-Gaspà, Riccardo Moia, Elı́as Campo, Cynthia K. Hahn, Pablo Bousquets‐Muñoz, Wolfgang K. Huber, Lydia Scarfò, Shimin Shuai, Tait D. Shanafelt, Marine Armand, Gianluca Gaïdano, Andrea Visentin, Marta Kulis, Michael Doubek, Κώστας Σταματόπουλος, Miguel Alcoceba, Viktor Ljungström, Catherine J. Wu, Marta Aymerich, Zadie Davis, Lincoln Stein, Larry Mansouri, Ferran Nadeu, Irene López‐Oreja, Enrique Colado, Binyamin A. Knisbacher, Thomas Chatzikonstantinou, Alfredo Rivas‐Delgado, María José Terol, Šárka Pospı́šilová, Ángel Ramírez Páyer, Karla Plevová, Anton W. Langerak, Marcos González, Junyan Lu, Cecilia Jylhä, Kari G. Rabe, Sı́lvia Beà, Daniel Hägerstrand, Ryan D. Morin, Dolors Colomer, Aron Skaftason, Anna Enjuanes, Paolo Ghia, Tycho Baumann, Xosé S. Puente, Emma Young, David Oscier, Armando López‐Guillermo, Ellen J. van Gastel-Mol
article en
1 citations

Abstract

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.

LeukemiaVol. 39(9)
Broad Institute (US), Ontario Institute for Cancer Research (CA), Institució Catalana de Recerca i Estudis Avançats (ES), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Uppsala University (SE), Brigham and Women's Hospital (US), Central European Institute of Technology (CZ), Karolinska University Hospital (SE), Harvard University (US), University of Padua (IT), Bar-Ilan University (IL), Vita-Salute San Raffaele University (IT), Universitat de València (ES), Universidad de Oviedo (ES), Simon Fraser University (CA), University of Toronto (CA), University of Zurich (CH), Masaryk University (CZ), Heidelberg University (DE), Barcelona Supercomputing Center (ES), Science for Life Laboratory (SE), Harvard University Press (US), Erasmus MC (NL), University Hospital Heidelberg (DE), Karolinska Institutet (SE), Southern University of Science and Technology (CN), Sorbonne Université (FR), Massachusetts General Hospital (US), Central European Institute of Technology – Masaryk University (CZ), Hospital Clínico Universitario de Valencia (ES), Departament de Salut (ES), University Hospital of Zurich (CH), Hospital Universitario 12 De Octubre (ES), Institute of Oncology Research (CH), University Hospital Brno (CZ), Hospital Clínic de Barcelona (ES), Dana-Farber Cancer Institute (US), Pitié-Salpêtrière Hospital (FR), Mayo Clinic in Arizona (US), Canada's Michael Smith Genome Sciences Centre (CA), IRCCS Ospedale San Raffaele (IT), Instituto de Investigación Biomédica de Salamanca (ES), Centre for Research and Technology Hellas (GR), Stanford Medicine (US), European Molecular Biology Laboratory (DE), Centro de Investigación del Cáncer (ES), Mayo Clinic in Florida (US), Center for Cancer Research (US), G. Papanikolaou General Hospital (GR), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Universitat de Barcelona (ES), Bournemouth University (GB), Universitat Politècnica de Catalunya (ES)
American Association for Cancer Research, Amgen, AstraZeneca, European Hematology Association, Centres de Recerca de Catalunya, European Commission, National Natural Science Foundation of China, Cancerfonden, Generalitat de Catalunya, Eusko Jaurlaritza, Ministerstvo Zdravotnictví Ceské Republiky, Institució Catalana de Recerca i Estudis Avançats, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Ministerio de Ciencia e Innovación, Associazione Italiana per la Ricerca sul Cancro, Radiumhemmets Forskningsfonder, Fundación Española de Hematología y Hemoterapia, Science for Life Laboratory, Southern University of Science and Technology, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Agència de Gestió d'Ajuts Universitaris i de Recerca, European Regional Development Fund, Agencia Estatal de Investigación
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Openalex Percentile: Top 16%
Chronic Lymphocytic Leukemia Research
1.63
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