Suk-young Lee, Keiki Kumano, Kumi Nakazaki, Masashi Sanada, Akihiko Matsumoto, Go Yamamoto, Yasuhito Nannya, Ritsuro Suzuki, Satoshi Ota, Yasunori Ota, Koji Izutsu, Mamiko Sakata-Yanagimoto, Akira Hangaishi, Hideo Yagita, Masashi Fukayama, Masao Seto, Mineo Kurokawa, Seishi Ogawa, Shigeru Chiba
CANCER SCIENCE, 100(5) 920-926, May, 2009 Peer-reviewed
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).