Frequent inactivation of A20 in B-cell lymphomas

Motohiro Kato, Masashi Sanada, Itaru Kato, Yasuharu Sato, Junko Takita, Kengo Takeuchi, Akira Niwa, Yuyan Chen, Kumi Nakazaki, Junko Nomoto, Yoshitaka Asakura, Satsuki Muto, Azusa Tamura, Mitsuru Iio, Yoshiki Akatsuka, Yasuhide Hayashi, Hiraku Mori, Takashi Igarashi, Mineo Kurokawa, Shigeru ChibaShigeo Mori, Yuichi Ishikawa, Koji Okamoto, Kensei Tobinai, Hitoshi Nakagama, Tatsutoshi Nakahata, Tadashi Yoshino, Yukio Kobayashi, Seishi Ogawa

Research output: Contribution to journalArticlepeer-review

414 Citations (Scopus)

Abstract

A20 is a negative regulator of the NF-B pathway and was initially identified as being rapidly induced after tumour-necrosis factor-α stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-B in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. 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 Hodgkins 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, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-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-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-B activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

Original languageEnglish
Pages (from-to)712-716
Number of pages5
JournalNature
Volume459
Issue number7247
DOIs
Publication statusPublished - Jun 4 2009

ASJC Scopus subject areas

  • General

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