Letter

Nature 459, 712-716 (4 June 2009) | doi:10.1038/nature07969; Received 17 September 2008; Accepted 3 March 2009; Published online 3 May 2009

Frequent inactivation of A20 in B-cell lymphomas

Motohiro Kato1,2, Masashi Sanada1,5, Itaru Kato6, Yasuharu Sato7, Junko Takita1,2,3, Kengo Takeuchi8, Akira Niwa6, Yuyan Chen1,2, Kumi Nakazaki1,4,5, Junko Nomoto9, Yoshitaka Asakura9, Satsuki Muto1, Azusa Tamura1, Mitsuru Iio1, Yoshiki Akatsuka11, Yasuhide Hayashi12, Hiraku Mori13, Takashi Igarashi2, Mineo Kurokawa4, Shigeru Chiba3, Shigeo Mori14, Yuichi Ishikawa8, Koji Okamoto10, Kensei Tobinai9, Hitoshi Nakagama10, Tatsutoshi Nakahata6, Tadashi Yoshino7, Yukio Kobayashi9 & Seishi Ogawa1,5

  1. Cancer Genomics Project, Department of,
  2. Pediatrics,
  3. Cell Therapy and Transplantation Medicine, and,
  4. Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
  5. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
  6. Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
  7. Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
  8. Division of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, Japan, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan
  9. Hematology Division, Hospital, and,
  10. Early Oncogenesis Research Project, Research Institute, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
  11. Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
  12. Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa 377-8577, Japan
  13. Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30, Fujigaoka, Aoba-ku, Yokohama-shi, Kanagawa 227-8501, Japan
  14. Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

Correspondence to: Yukio Kobayashi9Seishi Ogawa1,5 Correspondence and requests for materials should be addressed to S.O. (Email: sogawa-tky@umin.ac.jp) or Y.K. (Email: ykkobaya@ncc.go.jp).

A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation1. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli2, 3, 4, 5, 6, 7; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk8, 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, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB 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-kappaB 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-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.