Frequent inactivation of A20 in B-cell lymphomas
Frequent inactivation of A20 in B-cell lymphomas
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DOI：
10.1038/nature07969
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发表时间：
2009-06-04
期刊：
影响因子：
64.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
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作者：
Kato, Motohiro;Sanada, Masashi;Ogawa, Seishi
A20是NF-kappa B通路的负调节因子，最初被确定为在肿瘤坏死因子- α刺激后快速诱导(1)。它在调节免疫反应中起关键作用，防止NF-kappa B在各种外部刺激下过度激活（2-7）；最近的遗传学研究揭示了多态A20（也称为TNFAIP3）等位基因与自身免疫性疾病风险的推定关联（8,9）。然而，A20在人类癌症发展中的作用尚不清楚。通过对238例b细胞淋巴瘤的遗传病变进行全基因组分析，我们发现A20是b系淋巴瘤的常见遗传靶点。A20在粘膜相关组织淋巴瘤（87例中有18例，21.8%）和霍奇金淋巴瘤中经常因体细胞突变和/或缺失而失活。结节性硬化组织学（15例中有5例，33.3%），其他b系淋巴瘤较少。当在无A20等位基因的淋巴瘤来源细胞系中重新表达时，野生型A20，而不是突变型A20，导致细胞生长受到抑制，诱导凋亡，并伴有NF-kappa B激活的下调。A20缺陷细胞在免疫缺陷小鼠中稳定地产生肿瘤，而A20的重新表达有效地抑制了致瘤性。在A20缺乏的细胞中，由于A20的重新表达而抑制细胞生长和NF-kappa B活性，至少部分依赖于细胞表面受体信号传导，包括肿瘤坏死因子受体。考虑到A20在多种上游刺激诱导的NF-kappa B激活负调节中的生理功能，我们的研究结果表明，由A20功能丧失引起的NF-kappa B信号不受控制参与了B谱系淋巴瘤亚群的发病机制。
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.