期刊
CANCERS
卷 13, 期 21, 页码 -出版社
MDPI
DOI: 10.3390/cancers13215493
关键词
PPM1D; p53; genetically engineered mouse model; adenocarcinoma; lymphoma; neuroblastoma
类别
资金
- Swedish Childhood Cancer Foundation
- Swedish Research Council
- Swedish Cancer Foundation
- Swedish Foundation for Strategic Research
- Karolinska Institutet
- Maerta and Gunnar V Philipson Foundation
- Cancer Research Foundations of Radiumhemmet
- Swedish Cancer Foundation [CAN2018/460]
Overexpression of PPM1D in mice leads to a variety of cancers, with T-cell lymphoblastic lymphoma being the most common. These tumors show similarities in phenotype and genetics to tumors in mice with dysfunctional p53.
PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing PPM1D demonstrates Pten-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, Notch1 mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in PPM1D-transgenic mice. Hence, PPM1D acts as an oncogenic driver in connection with cellular stress, suggesting that the PPM1D gene status and expression levels should be investigated in TP53 wild-type tumors.
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