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Non-coding recurrent mutations in chronic lymphocytic leukaemia.
- Source :
-
Nature [Nature] 2015 Oct 22; Vol. 526 (7574), pp. 519-24. Date of Electronic Publication: 2015 Jul 22. - Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- 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 metabolism
Leukemia, Lymphocytic, Chronic, B-Cell pathology
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
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Mutation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 526
- Issue :
- 7574
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 26200345
- Full Text :
- https://doi.org/10.1038/nature14666