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Nature. 2015 Oct 22;526(7574):519-24. doi: 10.1038/nature14666. Epub 2015 Jul 22.

Non-coding recurrent mutations in chronic lymphocytic leukaemia.

Author information

  • 1Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
  • 2Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
  • 3Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
  • 4Departament d'Anatomía Patològica, Microbiología i Farmacología, Universitat de Barcelona, 08036 Barcelona, Spain.
  • 5Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
  • 6Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
  • 7Unidad de Genómica, IDIBAPS, 08036 Barcelona, Spain.
  • 8Servicio de Hematología, Hospital Clínic, IDIBAPS, 08036 Barcelona, Spain.
  • 9Institute for Cancer Genetics, Columbia University, New York 10032, USA.
  • 10Servicio de Hematología, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
  • 11Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), Hospital del Mar Research Institute (IMIM), 08003 Barcelona, Spain.
  • 12Servicio de Hematología, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain.
  • 13Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain.
  • 14Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del País Vasco, 48007 Bilbao, Spain.
  • 15Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, 28029 Madrid, Spain.
  • 16Institute of Applied Biosciences, Center for Research and Technology Hellas, 57001 Thermi, Thessaloniki, Greece.
  • 17Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands.
  • 18Servicio de Hematología, Hospital Clínico de Valencia, 46010 Valencia, Spain.


Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

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