文章：

慢性自然杀伤细胞淋巴细胞增殖性疾病的体细胞突变高清图谱

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

原文发布日期：2020-04-22

DOI: 10.1038/s41408-020-0309-2

类型: Article

开放获取: 是

英文摘要：

The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD‐NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1-negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.
 

摘要翻译： 

慢性自然杀伤（NK）细胞淋巴增殖性疾病（CLPD-NK）的分子发病机制尚不清楚。在对57名CLPD-NK患者进行筛查后，仅五名患者出现STAT3突变。对13例STAT3/STAT5B突变阴性的病例进行全外显子组测序（WES）分析，发现每名患者平均有18个克隆性、群体罕见且有害的体细胞变异。CLPD-NK的突变景观显示，大多数患者携带重突变负担，主要和亚克隆有害突变共存于白血病克隆中。体细胞突变首先影响与癌症增殖、存活和迁移通路相关的基因，包括Ras/MAPK、PI3K-AKT，以及JAK/STAT（如PIK3R1和PTK2）。我们确认了MAP10、MPZL1、RPS6KA1、SETD1B、TAOK2、TMEM127和TNFRSF1A基因的推定驱动变异，以及与病毒感染（DDX3X和RSF1）和DNA修复（PAXIP1）相关的基因。验证了表观遗传调节因子TET2的截断突变和可能废除PIK3R1负调控活性的变异。这项研究显著推进了对CLPD-NK涉及基因和通路的理解，表明与侵袭性NK细胞疾病的相似性，并检测到可被批准药物靶向的突变基因，是向CLPD-NK患者个性化精准医学迈出的一步。

原文链接：

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells