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Dominant-Negative Effect Detected for Missense TP53 Mutations in Myeloid Cancers

NEW YORK – Missense mutations in TP53 that have been reported in acute myeloid leukemia (AML) and other myeloid cancer types appear to have dominant-negative effects that dial down the activity of wild type TP53 in the same cells, new research suggests.

Investigators from the Dana-Farber Cancer Institute, Broad Institute, and elsewhere started by profiling TP53 missense mutations that have been described in individuals with high-risk forms of myelodysplastic syndrome (MDS), a condition that can progress to AML. After introducing half a dozen TP53 mutations into human leukemia cell lines with CRISPR-Cas9-based gene editing, they integrated additional functional and genomic data to demonstrate a dominant-negative effect for the mutations. From there, they expanded their analysis to screen for similar effects across a much broader set of missense mutations in the tumor suppressor gene.

Together, these and other findings "consistently indicate that TP53 missense mutations have dominant-negative activity without evidence of [gain-of-function] capacity," senior and corresponding author Benjamin Ebert, a medical oncology researcher affiliated with Dana-Farber, the Broad, and Brigham and Women's Hospital, and his colleagues wrote in their Science study.

"We therefore propose a model in which missense variants exert a [dominant-negative effect] that shapes the mutational spectrum early in the development of myeloid malignancies, often still at the premalignant stage," they added, "thereby providing a clonal reservoir of cells that are prone to expand and acquire secondary mutations, resulting in the development of myeloid malignancies."

Past studies suggest that the suite of somatic mutations that coincide with TP53 mutations can vary by cancer type, though an integrated pan-cancer genomic study reported recently in Cell Reports described a gene expression signature associated with outcomes in 11 cancer types involving TP53 mutations.

In another study published in PLOS One this month, researchers from Japan described somatic mutations affecting the FGFR3 and RAS genes, which are often found in non-muscle-invasive bladder cancers that occur in individuals with a specific TP53 mutation.

For their new study, the researchers used CRISPR-Cas9 editing to first introduce six missense TP53 mutations into two different AML cell lines, known as K562 and MOLM13. After finding hints that the missense changes in one TP53 gene could have a dominant-negative effect on the other copy of the gene, they screened all potential missense changes in TP53 in an AML cell line containing a green fluorescent protein-tagged copy of wild type p53 — producing amino acid changes that lined up with those described in more than 1,000 individuals with myeloid malignancies.

From there, the team exposed cells to varying concentrations of DNA-damaging chemotherapy drugs such as daunorubicin or compounds such as nutlin-3a, which interfere with the ability of the TP53 gene product p53 to bind MDM2, contributing to proteasomal degradation. It also tested TP53 mutations in other cell types and in mouse models, generating additional data that seemed to argue against a gain-of-function role for mutant TP53.

"Future studies aimed at elucidating the molecular mechanisms of the [dominant-negative effect] may lead to therapeutic strategies that prevent outgrowth of TP53-mutant clones and progression into AML and MDS," the authors wrote.

In a related perspectives article in Science, the Karolinska Institute's David Lane discussed the loss-of-function and dominant-negative effects that the TP53 missense mutations had in the myeloid cancer setting.

But, he cautioned against over-interpreting the results. For example, Lane pointed to the potential importance of TP53 gene dosage and noted that the dominant-negative effect reported "may be affected by the amount of p53 protein being expressed."