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

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Science  09 Aug 2019:
Vol. 365, Issue 6453, pp. 599-604
DOI: 10.1126/science.aax3649

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p53—still hazy after all these years?

The gene encoding the p53 tumor suppressor protein is the most frequently mutated gene in human cancer. Yet decades after the gene's discovery, the biology of cancer-associated missense mutations in p53 is still being debated. Previous studies have suggested that missense mutations confer tumor-promoting functions to p53. Boettcher et al. conducted a detailed analysis of p53 missense mutations in human leukemia, drawing on methodologies including genome editing, a p53 saturation mutagenesis screen, mouse models, and clinical data (see the Perspective by Lane). They found no evidence that p53 missense mutations confer an oncogenic gain of function. Rather, the mutations exerted a dominant-negative effect that reduced the tumor suppressor activity of wild-type p53.

Science, this issue p. 599; see also p. 539

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.

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