Non-coding recurrent mutations in chronic lymphocytic leukaemia
A partir d'échantillons sanguins prélevés sur 452 patients atteints d'une leucémie lymphocytaire chronique et sur 54 patients atteints d'une lymphocytose monoclonale de type B, cette étude identifie notamment de fréquentes mutations dans des régions non codantes du génome en lien avec des anomalies d'épissage et un comportement agressif de la maladie
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[prime] 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 [ge]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.