Non-coding recurrent mutations in chronic lymphocytic leukaemia
Non-coding recurrent mutations in chronic lymphocytic leukaemia
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DOI：
10.1038/nature14666
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发表时间：
2015-10-22
期刊：
影响因子：
64.8
通讯作者：
Campo, Elias
中科院分区：
文献类型：
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作者：
Puente, Xose S.;Bea, Silvia;Campo, Elias
慢性淋巴细胞白血病（CLL）是一种常见的疾病，其中决定临床生物学行为的遗传改变尚未完全了解。在这里，我们描述了452例慢性淋巴细胞白血病病例和54例单克隆B淋巴细胞增多症（一种前驱疾病）患者的基因组景观的综合评价。我们扩展了CLL驱动程序更改的数量，包括ZNF 292，ZMYM 3，ARID 1A和PTPN 11的更改。我们还鉴定了非编码区（包括NOTCH1的39区）中新的复发性突变，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，位于染色体9p13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。驾驶员改变的累积数量（0至>= 4）区分了临床行为差异的患者。这项研究提供了CLL基因组景观的综合画像，确定了疾病的新的复发驱动突变，并提出了可能改善这种瘤形成管理的临床干预措施。
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 39 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.