A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations

The shelterin protein POT1 has been found mutated in many different familial and sporadic cancers, however, no mouse models to understand the pathobiology of these mutations have been developed so far. To address the molecular mechanisms underlying the tumorigenic effects of POT1 mutant proteins in...

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Bibliographic Details
Published in:PLoS genetics 2022-06, Vol.18 (6), p.e1010260-e1010260
Main Authors: Martínez, Paula, Sánchez-Vázquez, Raúl, Ferrara-Romeo, Iole, Serrano, Rosa, Flores, Juana M., Blasco, Maria A.
Format: Article
Language:English
Subjects:
Animal models
Biology and Life Sciences
Cancer
Cell division
Chromosomes
Complementation
Embryo fibroblasts
Endothelial cells
Heart
Leukemia
Lymphoma
Medicine and Health Sciences
Melanoma
Molecular modelling
Mutants
Mutation
Proteins
Research and Analysis Methods
Telomerase
Telomeres
Tumors
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Summary:The shelterin protein POT1 has been found mutated in many different familial and sporadic cancers, however, no mouse models to understand the pathobiology of these mutations have been developed so far. To address the molecular mechanisms underlying the tumorigenic effects of POT1 mutant proteins in humans, we have generated a mouse model for the human POT1 R117C mutation found in Li-Fraumeni-Like families with cases of cardiac angiosarcoma by introducing this mutation in the Pot1a endogenous locus, knock-in for Pot1a R117C . We find here that both mouse embryonic fibroblasts (MEFs) and tissues from Pot1a +/ ki mice show longer telomeres than wild-type controls. Longer telomeres in Pot1a +/ ki MEFs are dependent on telomerase activity as they are not found in double mutant Pot1a +/ ki Tert -/- telomerase-deficient MEFs. By using complementation assays we further show that POT1a pR117C exerts dominant-negative effects at telomeres. As in human Li-Fraumeni patients, heterozygous Pot1a +/ ki mice spontaneously develop a high incidence of angiosarcomas, including cardiac angiosarcomas, and this is associated to the presence of abnormally long telomeres in endothelial cells as well as in the tumors. The Pot1a +/R117C mouse model constitutes a useful tool to understand human cancers initiated by POT1 mutations.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1010260