非整倍体
生物
癌变
癌症研究
清脆的
染色体
癌症
癌基因
三体
染色体不稳定性
遗传学
细胞周期
基因
作者
Vishruth Girish,Asad A. Lakhani,Christine M. Scaduto,Sarah L. Thompson,Leanne Brown,Ryan A. Hagenson,Erin L. Sausville,Brianna E. Mendelson,Devon A. Lukow,Monet Lou Yuan,Pranav K. Kandikuppa,Eric C. Stevens,Sophia N. Lee,Barbora Šalovská,Wenxue Li,Joan C. Smith,Alison M. Taylor,Robert A. Martienssen,Yansheng Liu,Ruping Sun,Jason M. Sheltzer
标识
DOI:10.1101/2023.01.09.523344
摘要
ABSTRACT Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses TP53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, specific aneuploidies play essential roles in tumorigenesis, raising the possibility that targeting these “aneuploidy addictions” could represent a novel approach for cancer treatment.
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