A comprehensive functional analysis of TP53 mutations in human leukemia may refute a working hypothesis - primarily based on mouse studies - that missense mutations confer new cancer-causing functions to the p53 tumor suppressor protein; the new study instead suggests that these mutations exert a "dominant-negative" effect that reduces the cancer-suppressing activity of wild-type p53, the authors say. The TP53 gene was discovered 40 years ago and it now known to be the most frequently mutated gene in human cancer. Initially, TP53 was mischaracterized as an oncogene but human genetic studies ultimately established that it encodes a tumor suppressor. But how cancer-associated mutations in TP53 alter the function of wild-type p53 has continued to be the subject of debate. The vast majority of TP53 mutations across all cancer types are missense mutations, which can result in non-functional or dysfunctional p53. Based largely on mouse model experiments, it has been hypothesized that certain missense mutations can transform the p53 tumor suppressor into a tumor promoter via so-called oncogenic "gain of function" (GOF) effects. To explore the functional consequences of p53 mutations, Steffen Boettcher and colleagues performed a comprehensive analysis of TP53 mutations in human myeloid leukemia. Using CRISPR/Cas9 gene editing technology, the authors generated isogenic human leukemia cell lines featuring the most common p53 missense variants. This isogenic analysis - as well as comprehensive mutational screening, in vivo experiments in mice and an analysis of clinical data - did not support the notion that missense mutations confer new oncogenic functions to the p53 tumor suppressor protein, according to Boettcher et al. Instead, the authors discovered that the mutations confer either loss of function effects or dominant-negative effects (DNE) that reduce the tumor-supressing efficacy of wild-type p53 in human leukemia. In a related Perspective, David Lane discusses the new results as well as the possible ways in which they can be reconciled with the findings of previous studies.