A dominant-negative effect drives selection of missense mutations in myeloid malignancies.
, 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 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 missense mutations. Thus, a DNE is the primary unit of selection for missense mutations in myeloid malignancies.
|Year of Publication||
2019 08 09
P01 CA066996 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U01 CA199253 / CA / NCI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States