p53-dependent non-coding RNA networks in chronic lymphocytic leukemia
p53-dependent non-coding RNA networks in chronic lymphocytic leukemia
复制标题
慢性淋巴细胞白血病中依赖p53的非编码RNA网络
DOI：
10.1038/leu.2015.119
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发表时间：
2015-10-01
期刊：
影响因子：
11.4
通讯作者：
Zenz, T.
中科院分区：
文献类型：
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作者：
Blume, C. J.;Hotz-Wagenblatt, A.;Zenz, T.
肿瘤抑制基因p53的突变导致慢性淋巴细胞白血病（CLL）的化疗耐药和预后不良。尽管p53靶点用于鉴定p53功能受损的患者亚组，但CLL中p53非编码RNA靶点的综合评估缺失。我们利用突变型p53的转录活性受损，通过小RNA测序绘制出CLL中的p53靶点。我们描述的景观p53依赖的microRNA/非编码RNA诱导的DNA损伤在CLL。除了关键的p53靶点miR-34 a外，我们还鉴定了一组依赖于p53的microRNA（miRNAs; miR-182- 5 p，miR-7- 5 p和miR-320 c/d）。除了miRNA之外，长非编码RNA（lncRNA）核富集丰富转录本1（NEAT 1）和长基因间非编码RNA p21（lincRNA-p21）在功能性p53存在下响应于DNA损伤而被诱导，但在具有p53突变的CLL中不被诱导。NEAT 1和lincRNA-p21的诱导与DNA损伤后细胞死亡的诱导密切相关。我们使用同基因淋巴瘤细胞系模型来证明NEAT 1和lincRNA-p21的p53依赖性。目前的工作描述了p53依赖性miRNome，并确定lncRNAs NEAT 1和lincRNA-p21作为CLL和淋巴瘤中p53依赖性DNA损伤反应机制的新元件。
Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of noncoding RNA targets of p53 in CLL is missing. We exploited the impaired transcriptional activity of mutant p53 to map out p53 targets in CLL by small RNA sequencing. We describe the landscape of p53-dependent microRNA/non-coding RNA induced in response to DNA damage in CLL. Besides the key p53 target miR-34a, we identify a set of p53-dependent microRNAs (miRNAs; miR-182-5p, miR-7-5p and miR-320c/d). In addition to miRNAs, the long non-coding RNAs (lncRNAs) nuclear enriched abundant transcript 1 (NEAT1) and long intergenic non-coding RNA p21 (lincRNA-p21) are induced in response to DNA damage in the presence of functional p53 but not in CLL with p53 mutation. Induction of NEAT1 and lincRNA-p21 are closely correlated to the induction of cell death after DNA damage. We used isogenic lymphoma cell line models to prove p53 dependence of NEAT1 and lincRNA-p21. The current work describes the p53-dependent miRNome and identifies lncRNAs NEAT1 and lincRNA-p21 as novel elements of the p53-dependent DNA damage response machinery in CLL and lymphoma.