A1 Refereed original research article in a scientific journal
A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies
Authors: Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivtsov AV, Giacomelli AO, Wong WH, Kim J, Chao S, Kurppa KJ, Yang XP, Milenkowic K, Piccioni F, Root DE, Rucker FG, Flamand Y, Neuberg D, Lindsley RC, Janne PA, Hahn WC, Jacks T, Dohner H, Armstrong SA, Ebert BL, Ebert BL
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publication year: 2019
Journal: Science
Journal name in source: SCIENCE
Journal acronym: SCIENCE
Volume: 365
Issue: 6453
First page : 599
Last page: +
Number of pages: 44
ISSN: 0036-8075
DOI: https://doi.org/10.1126/science.aax3649
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.
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