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哈佛大学团队发现白血病中TP53突变的功能

来 源:小柯机器人
发布时间:2019-08-09

美国哈佛大学Benjamin L。 Ebert研究团队在研究中取得进展。他们发现在髓系恶性肿瘤中,显性负抑制效应驱动了TP53错义突变的选择。 2019年8月9日出版的《科学》发表了这项成果。

研究人员使用CRISPR-Cas9产生最常见的TP53错义突变的同基因人类白血病细胞系。功能、DNA结合和转录分析表明功能的丧失但没有GOF效应。p53单氨基酸变体的综合突变筛选发现DNA结合域中的错义突变发挥显性负抑制效应(DNE)。在小鼠中,p53错义突变的DNE赋予造血细胞对DNA损伤的选择性优势。急性骨髓性白血病患者的临床结果分析显示没有TP53错义突变的GOF证据。因此,DNE是骨髓恶性肿瘤中TP53错义突变主要的选择。

据悉,TP53是人类癌症中最常见的突变基因,其编码肿瘤抑制因子p53。由错义突变主导的选择性压力塑造其突变谱,但仍了解甚少,并且其涉及新形态的功能获得(GOF)行为。

附:英文原文

Title: A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies

Author: Steffen Boettcher, Peter G. Miller, Rohan Sharma, Marie McConkey, Matthew Leventhal, Andrei V. Krivtsov, Andrew O. Giacomelli, Waihay Wong, Jesi Kim, Sherry Chao, Kari J. Kurppa, Xiaoping Yang, Kirsten Milenkowic, Federica Piccioni, David E. Root, Frank G. Rücker, Yael Flamand, Donna Neuberg, R. Coleman Lindsley, Pasi A. Jnne, William C. Hahn, Tyler Jacks, Hartmut Dhner, Scott A. Armstrong, Benjamin L. Ebert

Issue&Volume: Vol. 365, Issue 6453, pp. 599-604

Abstract: TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single–amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.

DOI: 10.1126/science.aax3649

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期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037
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