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

Zobrazit více v PubMed

Shuai S, Suzuki H, Diaz-Navarro A, Nadeu F, Kumar SA, Gutierrez-Fernandez A, et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature. 2019;574:712–6. PubMed

Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019;574:707–11. PubMed PMC

Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840–7. PubMed

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54. PubMed

Knisbacher BA, Lin Z, Hahn CK, Nadeu F, Duran-Ferrer M, Stevenson KE, et al. Molecular map of chronic lymphocytic leukemia and its impact on outcome. Nat Genet. 2022;54:1664–74. PubMed PMC

Kulis M, Heath S, Bibikova M, Queirós AC, Navarro A, Clot G, et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat Genet. 2012;44:1236–42. PubMed

Oakes CC, Seifert M, Assenov Y, Gu L, Przekopowitz M, Ruppert AS, et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet. 2016;48:253–64. PubMed PMC

Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–24. PubMed

Dietrich S, Oleś M, Lu J, Sellner L, Anders S, Velten B, et al. Drug-perturbation-based stratification of blood cancer. J Clin Invest. 2018;128:427–45. PubMed PMC

Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–30. PubMed PMC

Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood. 2013;122:1256–65. PubMed PMC

Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK, et al. Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nat Commun. 2018;9:4001. PubMed PMC

ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020;578:82–93. PubMed PMC

Grande BM, Gerhard DS, Jiang A, Griner NB, Abramson JS, Alexander TB, et al. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood. 2019;133:1313–24. PubMed PMC

Nadeu F, Martin-Garcia D, Clot G, Díaz-Navarro A, Duran-Ferrer M, Navarro A, et al. Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes. Blood. 2020;136:1419–32. PubMed PMC

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11. PubMed

Tobin G, Thunberg U, Johnson A, Thorn I, Soderberg O, Hultdin M, et al. Somatically mutated Ig VH3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood. 2002;99:2262–4. PubMed

Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T, et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood. 2007;109:259–70. PubMed

Maity PC, Bilal M, Koning MT, Young M, van Bergen CAM, Renna V, et al. IGLV3-21*01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling. Proc Natl Acad Sci USA. 2020;117:4320–7. PubMed PMC

Nadeu F, Royo R, Clot G, Duran-Ferrer M, Navarro A, Martín S, et al. IGLV3-21R110 identifies an aggressive biological subtype of chronic lymphocytic leukemia with intermediate epigenetics. Blood. 2021;137:2935–46. PubMed PMC

Syrykh C, Pons-Brun B, Russiñol N, Playa-Albinyana H, Baumann T, Duran-Ferrer M, et al. IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia. Blood Adv. 2023;7:7384–91. PubMed PMC

Nadeu F, Clot G, Delgado J, Martín-García D, Baumann T, Salaverria I, et al. Clinical impact of the subclonal architecture and mutational complexity in chronic lymphocytic leukemia. Leukemia. 2018;32:645–53. PubMed PMC

Strefford JC, Sutton L-A, Baliakas P, Agathangelidis A, Malčíková J, Plevova K, et al. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia. 2013;27:2196–9. PubMed

Sutton L-A, Young E, Baliakas P, Hadzidimitriou A, Moysiadis T, Plevova K, et al. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors. Haematologica. 2016;101:959–67. PubMed PMC

Stamatopoulos B, Smith T, Crompot E, Pieters K, Clifford R, Mraz M, et al. The light chain IgLV3-21 defines a new poor prognostic subgroup in chronic lymphocytic leukemia: results of a multicenter study. Clin Cancer Res. 2018;24:5048–57. PubMed

Ramsay AJ, Rodríguez D, Villamor N, Kwarciak A, Tejedor JR, Valcárcel J, et al. Frequent somatic mutations in components of the RNA processing machinery in chronic lymphocytic leukemia. Leukemia. 2013;27:1600–3. PubMed

Wan Y, Wu CJ. SF3B1 mutations in chronic lymphocytic leukemia. Blood. 2013;121:4627–34. PubMed PMC

Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396–407. PubMed PMC

Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679–90. PubMed PMC

López C, Kleinheinz K, Aukema SM, Rohde M, Bernhart SH, Hübschmann D, et al. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma. Nat Commun. 2019;10:1459. PubMed PMC