| Literature DB >> 31395785 |
Steffen Boettcher1,2,3, Peter G Miller1,2,3, Rohan Sharma2,3, Marie McConkey2,3, Matthew Leventhal2,3, Andrei V Krivtsov4, Andrew O Giacomelli1,2,5, Waihay Wong2,3, Jesi Kim3, Sherry Chao2,6, Kari J Kurppa1,7, Xiaoping Yang2, Kirsten Milenkowic2, Federica Piccioni2, David E Root2, Frank G Rücker8, Yael Flamand9, Donna Neuberg9, R Coleman Lindsley1,2, Pasi A Jänne1,7, William C Hahn1,2, Tyler Jacks10,11,12, Hartmut Döhner8, Scott A Armstrong4, Benjamin L Ebert13,2,3,14.
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.Entities:
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Year: 2019 PMID： 31395785 PMCID： PMC7327437 DOI： 10.1126/science.aax3649
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728