Frequent inactivation of A20 in B-cell lymphomas

被引：441

作者：

Kato, Motohiro ^{[1
,2
]}

Sanada, Masashi ^{[1
,5
]}

Kato, Itaru ^{[6
]}

Sato, Yasuharu ^{[7
]}

Takita, Junko ^{[1
,2
,3
]}

Takeuchi, Kengo ^{[8
]}

Niwa, Akira ^{[6
]}

Chen, Yuyan ^{[1
,2
]}

Nakazaki, Kumi ^{[1
,4
,5
]}

Nomoto, Junko ^{[9
]}

Asakura, Yoshitaka ^{[9
,11
]}

Muto, Satsuki ^{[1
]}

Tamura, Azusa ^{[1
]}

Iio, Mitsuru ^{[1
]}

Akatsuka, Yoshiki

Hayashi, Yasuhide ^{[12
]}

Mori, Hiraku ^{[13
]}

Igarashi, Takashi ^{[2
]}

Kurokawa, Mineo ^{[4
]}

Chiba, Shigeru ^{[3
]}

Mori, Shigeo ^{[14
]}

Ishikawa, Yuichi ^{[8
]}

Okamoto, Koji ^{[10
]}

Tobinai, Kensei ^{[9
]}

Nakagama, Hitoshi ^{[10
]}

Nakahata, Tatsutoshi ^{[6
]}

Yoshino, Tadashi ^{[7
]}

Kobayashi, Yukio ^{[9
]}

Ogawa, Seishi ^{[1
,5
]}

机构：

[1] Univ Tokyo, Canc Genom Project, Bunkyo Ku, Tokyo 1138655, Japan

[2] Univ Tokyo, Dept Pediat, Bunkyo Ku, Tokyo 1138655, Japan

[3] Univ Tokyo, Dept Cell Therapy & Transplantat Med, Bunkyo Ku, Tokyo 1138655, Japan

[4] Univ Tokyo, Dept Hematol & Oncol, Grad Sch Med, Bunkyo Ku, Tokyo 1138655, Japan

[5] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Kawaguchi, Saitama 3320012, Japan

[6] Kyoto Univ, Grad Sch Med, Dept Pediat, Sakyo Ku, Kyoto 6068507, Japan

[7] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pathol, Kita Ku, Okayama 7008558, Japan

[8] Japanese Fdn Canc Res, Inst Canc, Div Pathol, Koto Ku, Tokyo 1358550, Japan

[9] Natl Canc Ctr, Div Hematol, Chuo Ku, Tokyo 1040045, Japan

[10] Natl Canc Ctr, Early Oncogenesis Res Project, Res Inst, Chuo Ku, Tokyo 1040045, Japan

[11] Aichi Canc Ctr, Res Inst, Div Immunol, Chikusa Ku, Nagoya, Aichi 4648681, Japan

[12] Gunma Childrens Med Ctr, Shibukawa 3778577, Japan

[13] Showa Univ, Fujigaoka Hosp, Div Hematol, Aoba Ku, Yokohama, Kanagawa 2278501, Japan

[14] Teikyo Univ, Sch Med, Dept Pathol, Itabashi Ku, Tokyo 1738605, Japan

来源：

NATURE | 2009年 / 459卷 / 7247期

基金：

日本科学技术振兴机构;

关键词：

NF-KAPPA-B; CLASSICAL HODGKIN LYMPHOMA; SYSTEMIC-LUPUS-ERYTHEMATOSUS; NECROSIS FACTOR-ALPHA; ZINC-FINGER PROTEIN; EPSTEIN-BARR-VIRUS; ACTIVATION; TNFAIP3; GENE; INHIBITOR;

D O I：

10.1038/nature07969

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A20 is a negative regulator of the NF-kappa B pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation(1). It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappa B in response to a variety of external stimuli(2-7); recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk(8,9). However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of ;nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wildtype A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by down-regulation of NF-kappa B activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappa B activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappa B activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappa B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

引用

页码：712 / U118

页数：6

共 29 条

[1] The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses [J].