Ppm1d-KO Mouse

PPM1D, also known as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cδ), is a serine/threonine phosphatase. It negatively regulates crucial cancer suppressor pathways, especially those related to the DNA damage response, including the tumor suppressor p53 [2,4].

Using conditional mouse models, researchers found that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses [1]. In vitro and in vivo experiments showed that loss of Ppm1d sensitizes leukemias to cytotoxic therapies, even without a Ppm1d mutation [1]. In addition, in Diffuse Midline Gliomas (DMGs), PPM1D truncating mutations that increase phosphatase stability act as clonal driver events, and PPM1D phosphatase activity is required for in vivo oncogenesis [3].

In conclusion, PPM1D is an important regulator in the DNA damage response and cancer-related pathways. Conditional mouse models have revealed its role in hematopoiesis and gliomagenesis, suggesting its potential as a therapeutic target in myeloid malignancy and gliomas [1,3].

References:

1. Miller, Peter G, Sperling, Adam S, Mayerhofer, Christina, Lindsley, R Coleman, Ebert, Benjamin L. . PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy. In Blood, 142, 2079-2091. doi:10.1182/blood.2023020331. https://pubmed.ncbi.nlm.nih.gov/37595362/

2. Deng, Wenhong, Li, Jieqing, Dorrah, Kimberly, Vadgama, Jay, Wu, Yong. 2020. The role of PPM1D in cancer and advances in studies of its inhibitors. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 125, 109956. doi:10.1016/j.biopha.2020.109956. https://pubmed.ncbi.nlm.nih.gov/32006900/

3. Khadka, Prasidda, Reitman, Zachary J, Lu, Sophie, Phoenix, Timothy N, Bandopadhayay, Pratiti. 2022. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. In Nature communications, 13, 604. doi:10.1038/s41467-022-28198-8. https://pubmed.ncbi.nlm.nih.gov/35105861/

4. Husby, Simon, Hjermind Justesen, Emma, Grønbæk, Kirsten. 2020. Protein phosphatase, Mg2+/Mn2+-dependent 1D (PPM1D) mutations in haematological cancer. In British journal of haematology, 192, 697-705. doi:10.1111/bjh.17120. https://pubmed.ncbi.nlm.nih.gov/33616916/