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Abstract

A20 is a negative regulator of the NF-κB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-α stimulation1. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-κB 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-κB 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-κB 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-κB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-κB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

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Gene Expression Omnibus

Data deposits

The copy number data as well as the raw microarray data will be accessible from the GEO (http://ncbi.nlm.nih.gov/geo/) with the accession number GSE12906.

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Acknowledgements

This work was supported by the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, by the 21st century centre of excellence program ‘Study on diseases caused by environment/genome interactions’, and by Grant-in-Aids from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Ministry of Health, Labor and Welfare of Japan for the 3rd-term Comprehensive 10-year Strategy for Cancer Control. We also thank Y. Ogino, E. Matsui and M. Matsumura for their technical assistance.

Author Contributions M.Ka., K.N. and M.S. performed microarray experiments and subsequent data analyses. M.Ka., Y.C., K.Ta., J.T., J.N., M.I., A.T. and Y.K. performed mutation analysis of A20. M.Ka., S.Mu., M.S., Y.C. and Y.Ak. conducted functional assays of mutant A20. Y.S., K.Ta., Y.As., H.M., M.Ku., S.Mo., S.C., Y.K., K.To. and Y.I. prepared tumour specimens. I.K., K.O., A.N., H.N. and T.N. conducted in vivo tumorigenicity experiments in NOG/SCID mice. T.I., Y.H., T.Y., Y.K. and S.O. designed overall studies, and S.O. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Affiliations

  1. Cancer Genomics Project, Department of,

    • Motohiro Kato
    • , Masashi Sanada
    • , Junko Takita
    • , Yuyan Chen
    • , Kumi Nakazaki
    • , Satsuki Muto
    • , Azusa Tamura
    • , Mitsuru Iio
    •  & Seishi Ogawa
  2. Pediatrics,

    • Motohiro Kato
    • , Junko Takita
    • , Yuyan Chen
    •  & Takashi Igarashi
  3. Cell Therapy and Transplantation Medicine, and,

    • Junko Takita
    •  & Shigeru Chiba
  4. Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

    • Kumi Nakazaki
    •  & Mineo Kurokawa
  5. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan

    • Masashi Sanada
    • , Kumi Nakazaki
    •  & Seishi Ogawa
  6. Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

    • Itaru Kato
    • , Akira Niwa
    •  & Tatsutoshi Nakahata
  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

    • Yasuharu Sato
    •  & Tadashi Yoshino
  8. Division of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, Japan, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan

    • Kengo Takeuchi
    •  & Yuichi Ishikawa
  9. Hematology Division, Hospital, and,

    • Junko Nomoto
    • , Yoshitaka Asakura
    • , Kensei Tobinai
    •  & Yukio Kobayashi
  10. Early Oncogenesis Research Project, Research Institute, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

    • Koji Okamoto
    •  & Hitoshi Nakagama
  11. Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan

    • Yoshiki Akatsuka
  12. Gunma Children’s Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa 377-8577, Japan

    • Yasuhide Hayashi
  13. Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30, Fujigaoka, Aoba-ku, Yokohama-shi, Kanagawa 227-8501, Japan

    • Hiraku Mori
  14. Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

    • Shigeo Mori

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Correspondence to Yukio Kobayashi or Seishi Ogawa.

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    Supplementary Information

    This file contains Supplementary Tables 1-6, Supplementary Figures 1-10 with Legends, and a Supplementary Reference.

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https://doi.org/10.1038/nature07969

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