| Autor: |
Girish V; Yale University School of Medicine, New Haven, CT 06511.; Johns Hopkins University School of Medicine, Baltimore, MD 21205., Lakhani AA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724., Scaduto CM; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724., Thompson SL; Yale University School of Medicine, New Haven, CT 06511., Brown LM; Yale University School of Medicine, New Haven, CT 06511., Hagenson RA; Yale University School of Medicine, New Haven, CT 06511., Sausville EL; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724., Mendelson BE; Yale University School of Medicine, New Haven, CT 06511., Lukow DA; Yale University School of Medicine, New Haven, CT 06511., Yuan ML; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724., Kandikuppa PK; Yale University School of Medicine, New Haven, CT 06511., Stevens EC; Yale University School of Medicine, New Haven, CT 06511., Lee SN; Yale University School of Medicine, New Haven, CT 06511., Salovska B; Yale University School of Medicine, New Haven, CT 06511., Li W; Yale University School of Medicine, New Haven, CT 06511., Smith JC; Yale University School of Medicine, New Haven, CT 06511., Taylor AM; Columbia University School of Medicine, New York, NY 10032., Martienssen RA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Liu Y; Yale University School of Medicine, New Haven, CT 06511., Sun R; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455., Sheltzer JM; Yale University School of Medicine, New Haven, CT 06511. |
| Abstrakt: |
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. |
