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Blood, 17 September 2009, Vol. 114, No. 12, pp. 2467-2475.
Prepublished online as a Blood First Edition Paper on July 16, 2009; DOI 10.1182/blood-2008-12-194852.
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LYMPHOID NEOPLASIA
TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas
Keiichiro Honma1,
Shinobu Tsuzuki1,
Masao Nakagawa1,
Hiroyuki Tagawa1,
Shigeo Nakamura2,
Yasuo Morishima3, and
Masao Seto1,4
1 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya;
2 Pathology/Clinical Laboratories, Nagoya University Hospital, Nagoya;
3 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya; and
4 Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan
The constitutive activation of nuclear factor- B (NF-B) has been implicated in tumorigenesis of lymphoid malignancies. We have previously shown that chromosome 6q was frequently deleted in ocular marginal zone B-cell lymphoma and identified TNFAIP3/A20, a negative regulator of NF-B pathways, as the primary target for 6q deletion. In the study reported here, we extended the analysis to other subsets of non-Hodgkin lymphomas and found that A20 is frequently deleted in mantle cell lymphoma and diffuse large B-cell lymphoma. Importantly, A20 promoter methylation or gene mutation is also frequently detected in these lymphomas, raising the possibility that inactivation of A20 may be involved in lymphomagenesis. To address this question, we conducted overexpression experiments in lymphoma cell lines with A20 deletion and down-regulated expression of A20 with an siRNA technique in Epstein-Barr virus–infected lymphoblastoid cell lines. These experiments found that overexpression of A20 induced apoptosis and silencing of A20 was associated with resistance to apoptosis and enhanced clonogenicity. The cells with down-regulated A20 exhibited enhanced NF-B activities, which may account for the observed effects. These results indicate that our study provides a novel insight into molecular mechanisms leading to lymphoma and that specific targeting of NF-B pathways may be advantageous for treatment.
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[Abstract]
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