Gain-of-function mutations and copy number  increases of Notch2 in diffuse large B-cell lymphoma.
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.
Lee
Suk-young
SY
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan.
Kumano
Keiki
K
Nakazaki
Kumi
K
Sanada
Masashi
M
Matsumoto
Akihiko
A
Yamamoto
Go
G
Nannya
Yasuhito
Y
Suzuki
Ritsuro
R
Ota
Satoshi
S
Ota
Yasunori
Y
Izutsu
Koji
K
Sakata-Yanagimoto
Mamiko
M
Hangaishi
Akira
A
Yagita
Hideo
H
Fukayama
Masashi
M
Seto
Masao
M
Kurokawa
Mineo
M
Ogawa
Seishi
S
Chiba
Shigeru
S
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
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