期刊
CANCER SCIENCE
卷 100, 期 5, 页码 920-926出版社
WILEY
DOI: 10.1111/j.1349-7006.2009.01130.x
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [18013012, 19390258]
- Sagawa Foundation for the Promotion of Cancer Research
- Osaka Cancer Foundation
- Grants-in-Aid for Scientific Research [18013012, 19390258] Funding Source: KAKEN
Signaling through the Notch1 receptor has a pivotal role in early thymocyte development. Gain of Notch1 function results in the development of T-cell acute lymphoblastic leukemia in a number of mouse experimental models, and activating Notch1 mutations deregulate Notch1 signaling in the majority of human T-cell acute lymphoblastic leukemias. Notch2, another member of the Notch gene family, is preferentially expressed in mature B cells and is essential for marginal zone B-cell generation. Here, we report that 5 of 63 (similar to 8%) diffuse large B-cell lymphomas, a subtype of mature B-cell lymphomas, have Notch2 mutations. These mutations lead to partial or complete deletion of the proline-, glutamic acid-, serine- and threonine-rich (PEST) domain, or a single amino acid substitution at the C-terminus of Notch2 protein. Furthermore, high-density oligonucleotide microarray analysis revealed that some diffuse large B-cell lymphoma cases also have increased copies of the mutated Notch2 allele. In the Notch activation-sensitive luciferase reporter assay in vitro, mutant Notch2 receptors show increased activity compared with wild-type Notch2. These findings implicate Notch2 gain-of-function mutations in the pathogenesis of a subset of B-cell lymphomas, and suggest broader roles for Notch gene mutations in human cancers. (Cancer Sci 2009; 100: 920-926).
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