title: Gain-of-function mutations and copy number  increases of Notch2 in diffuse large B-cell lymphoma.
abstract: 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 (approximately 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.
authors.affiliation: Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Suk-young
authors.initials: SY
authors.lastname: Lee
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Kumi
authors.initials: K
authors.lastname: Nakazaki
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Go
authors.initials: G
authors.lastname: Yamamoto
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nannya
authors.forename: Ritsuro
authors.initials: R
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ota
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ota
authors.forename: Koji
authors.initials: K
authors.lastname: Izutsu
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Hangaishi
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D015260:Neprilysin / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D015260:Neprilysin; D051560:Proto-Oncogene Proteins c-bcl-6; D051883:Receptor, Notch2; D000099218:Interferon Regulatory Factor-4; C084103:BCL6 protein, human; C497764:NOTCH2 protein, human