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.

Barcelona Supercomputing Center Barcelona Spain

Biología Molecular e Histocompatibilidad IBSAL Hospital Universitario Centro de Investigación del Cáncer IBMCC Salamanca Spain

Canada's Michael Smith Genome Sciences Centre British Columbia Cancer Agency Vancouver BC Canada

Center for Cancer Research Massachusetts General Hospital Boston MA USA

Central European Institute of Technology Masaryk University Brno Czech Republic

Centro de Investigación Biomédica en Red de Cáncer Barcelona Spain

Clinical Genetics and Genomics Karolinska University Hospital Stockholm Sweden

Computational Biology Program Ontario Institute for Cancer Research Toronto ON Canada

Departamento de Bioquímica y Biología Molecular Instituto Universitario de Oncología Universidad de Oviedo Oviedo Spain

Department of Data Science Dana Farber Cancer Institute Boston MA USA

Department of Haematology University Hospitals Dorset Bournemouth UK

Department of Hematology Oncology Institute of Southern Switzerland and Institute of Oncology Research Bellinzona Switzerland

Department of Human Cell Biology and Genetics School of Medicine Southern University of Science and Technology Shenzhen China

Department of Immunology Erasmus MC University Medical Center Rotterdam Netherlands

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Internal Medicine Hematology and Oncology Faculty of Medicine Masaryk University and University Hospital Brno Brno Czech Republic

Department of Laboratory Medicine and Pathology Hospital Pitie Salpetriere Sorbonne University Paris France

Department of Medical Oncology and Hematology University Hospital and University of Zurich Zurich Switzerland

Department of Medical Oncology Dana Farber Cancer Institute Boston MA USA

Department of Medicine Brigham and Women's Hospital Boston MA USA

Department of Medicine Hematology unit University of Padua Padua Italy

Department of Molecular Biology and Biochemistry Simon Fraser University Burnaby BC Canada

Department of Molecular Genetics University of Toronto Toronto ON Canada

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Molecular Pathology University Hospitals Dorset Bournemouth UK

Department of Pathology Massachusetts General Hospital Boston MA USA

Department of Quantitative Health Sciences Division of Clinical Trials and Biostatistics Mayo Clinic Rochester MN USA

Division of Hematology Department of Translational Medicine University of Eastern Piedmont Novara Italy

Division of Hematology Mayo Clinic Rochester MN USA

European Molecular Biology Laboratory Heidelberg Germany

Facultat de Medicina i Ciències de la Salut Universitat de Barcelona Barcelona Spain

Harvard Medical School Boston MA USA

Harvard University Cambridge MA USA

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hospital Clínic of Barcelona Barcelona Spain

Hospital Universitario 12 de Octubre Madrid Spain

Institució Catalana de Recerca i Estudis Avançats Barcelona Spain

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece

Institute of Medical Genetics and Genomics Faculty of Medicine Masaryk University and University Hospital Brno Brno Czech Republic

Instituto de Investigación Biomédica de Salamanca Salamanca Spain

Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

Servicio de Hematología Hospital Clínico Universitario INCLIVA Universidad de Valencia Valencia Spain

Servicio de Hematología y Hemoterapia Hospital Universitario Central de Asturias; Instituto Universitario de Oncología del Principado de Asturias Oviedo Spain

Stanford School of Medicine Stanford CA USA

Strategic Research Program on CLL IRCCS San Raffaele Hospital Milano Italy

The Broad Institute of MIT and Harvard Cambridge MA USA

The Mina and Everard Goodman Faculty of Life Sciences Bar Ilan University Ramat Gan Israel

Università Vita Salute San Raffaele Milano Italy

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