Non-coding recurrent mutations in chronic lymphocytic leukaemia

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Alternative Splicing / genetics
  • B-Lymphocytes / metabolism
  • Carrier Proteins / genetics
  • Chromosomes, Human, Pair 9 / genetics
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics
  • DNA-Binding Proteins
  • Enhancer Elements, Genetic / genetics
  • Genomics
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • PAX5 Transcription Factor / biosynthesis
  • PAX5 Transcription Factor / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Transcription Factors / genetics


  • 3' Untranslated Regions
  • ARID1A protein, human
  • Carrier Proteins
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • NOTCH1 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • PAX5 Transcription Factor
  • PAX5 protein, human
  • Receptor, Notch1
  • Transcription Factors
  • ZMYM3 protein, human
  • ZNF292 protein, human
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11