Notch2 is a gene with significant roles in multiple biological processes. It is expressed in many cell types within the hematolymphoid compartment and is crucial for the development of splenic marginal zone B cells, regulation of dendritic cell differentiation in the spleen, and plays specific roles in intestinal immunity. Notch2 also influences helper T cell divergence and cytotoxic T cell activation, operating within the Notch signaling pathway which is a cell-cell communication system [3].

In diseases, mutations in Notch2 have been implicated. In diffuse large B-cell lymphoma (DLBCL), certain mutations cause the protein to escape ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway, promoting chemoresistance [1]. In Alagille syndrome, a multisystem autosomal dominant disorder, pathogenic variants in Notch2 can disrupt normal Notch signaling [2,5]. In hepatocellular carcinoma, neutrophil extracellular traps promote immune escape by up-regulating CD73 through Notch2 activation [4]. Additionally, in a rare non-small cell lung carcinoma with diffuse coexpression of TTF1 and p40 in the same tumor cells, Notch2 mutations were detected, potentially offering new therapeutic possibilities [6]. In gastric adenocarcinoma, high expression of Notch2 is associated with early cancer stages, suggesting it could be a diagnostic target [7].

In conclusion, Notch2 is essential for the normal differentiation and function of various immune cells and is involved in multiple disease-related processes. The study of Notch2, especially through the analysis of its mutations in different disease models, helps in understanding disease mechanisms and potentially developing targeted therapies for diseases such as lymphoma, Alagille syndrome, hepatocellular carcinoma, and certain lung and gastric cancers.

References:

1. Zhou, Nan, Choi, Jaewoo, Grothusen, Grant, Wan, Liling, Busino, Luca. . DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. In Blood, 142, 973-988. doi:10.1182/blood.2022018752. https://pubmed.ncbi.nlm.nih.gov/37235754/

2. Gilbert, Melissa A, Bauer, Robert C, Rajagopalan, Ramakrishnan, Loomes, Kathleen M, Spinner, Nancy B. 2019. Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. In Human mutation, 40, 2197-2220. doi:10.1002/humu.23879. https://pubmed.ncbi.nlm.nih.gov/31343788/

3. Sakata-Yanagimoto, Mamiko, Chiba, Shigeru. . Notch2 and immune function. In Current topics in microbiology and immunology, 360, 151-61. doi:10.1007/82_2012_235. https://pubmed.ncbi.nlm.nih.gov/22695918/

4. Yu, Yang, Zhang, Congyi, Dong, Bowen, Wu, Dehai, Tai, Sheng. 2024. Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2. In Cancer letters, 598, 217098. doi:10.1016/j.canlet.2024.217098. https://pubmed.ncbi.nlm.nih.gov/38969159/

5. Mitchell, Ellen, Gilbert, Melissa, Loomes, Kathleen M. 2018. Alagille Syndrome. In Clinics in liver disease, 22, 625-641. doi:10.1016/j.cld.2018.06.001. https://pubmed.ncbi.nlm.nih.gov/30266153/

6. Guo, Xingmei, Dong, Lei, Liu, Hengan, Chen, Xiaoyan. 2022. TP53, NOTCH2, and STK11 Mutations in a Rare Tumor of non-Small Cell Lung Carcinoma with Diffuse Coexpression of TTF1 and p40 in the Same Tumor Cells. In International journal of surgical pathology, 31, 1041-1047. doi:10.1177/10668969221126105. https://pubmed.ncbi.nlm.nih.gov/36253711/

7. Li, Mei, He, Wenting, Wang, Furong, Liu, Tao, Li, Yumin. 2024. High expression of NOTCH2 in gastric adenocarcinoma: A novel early diagnostic target. In Journal of gastroenterology and hepatology, 39, 1115-1122. doi:10.1111/jgh.16540. https://pubmed.ncbi.nlm.nih.gov/38577711/