Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
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.
慢性淋巴细胞白血病（CLL）是一种常见疾病，其决定临床生物学行为的遗传改变尚未完全阐明。在这里，我们描述了对 452 例 CLL 病例和 54 例单克隆 B 淋巴细胞增多症（一种前驱疾病）患者的基因组景观进行的全面评估。我们扩展了 CLL 驱动突变的数量，包括 ZNF292、ZMYM3、ARID1A 和 PTPN11 的改变。我们还在非编码区域中发现了新的重复突变，包括 NOTCH1 的 3'区域，这些突变导致异常剪接事件，增加 NOTCH1 活性，并导致更具侵袭性的疾病。此外，位于 9p13 染色体上的增强子中的突变导致 B 细胞特异性转录因子 PAX5 的表达减少。驱动突变的累积数量（0 至≥4）可区分具有不同临床行为的患者。这项研究提供了 CLL 基因组景观的综合描述，确定了该疾病新的重复驱动突变，并提出了可能改善这种肿瘤管理的临床干预措施。
