TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.
TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.
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TNFAIP3（A20）是霍奇金淋巴瘤和原发性纵隔B细胞淋巴瘤中的肿瘤抑制基因。
DOI：
10.1084/jem.20090528
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发表时间：
2009-05-11
期刊：
影响因子：
--
通讯作者：
Küppers R
中科院分区：
文献类型：
--
作者：
Schmitz R;Hansmann ML;Bohle V;Martin-Subero JI;Hartmann S;Mechtersheimer G;Klapper W;Vater I;Giefing M;Gesk S;Stanelle J;Siebert R;Küppers R
霍奇金细胞和Reed/Sternberg细胞是经典霍奇金淋巴瘤的恶性细胞，其增殖和存活依赖于核因子κB(NF-κB)的结构性激活。通过各种刺激激活的NF-κB受锌指蛋白A20的负调控。为了确定A20是否在CHL的发病机制中起作用，我们在HL细胞系和激光显微切割的CHL活检HRS细胞中对编码A20的TNFAIP3进行了测序。我们在36个CHL中检测到16个(44%)体细胞突变，包括16个EB病毒阳性CHL中2个的错义突变和20个EB病毒−CHL中14个EBV CHL的错义突变、无义突变和移码插入或缺失。在大多数突变病例中，两个TNFAIP3等位基因都失活，包括频繁的TNFAIP3染色体缺失。野生型TNFAIP3在A20缺失的CHL细胞系中的重组显示，选定的NF-κB靶基因的转录显著减少，并引起细胞毒性。将突变分析扩展到另一种具有结构性NF-κB活性的淋巴瘤--原发性纵隔B细胞淋巴瘤，发现14例中有5例发生破坏性突变(36%)。本研究发现核因子-κB活性的关键调节基因TnFAIP3(A20)是一个新的肿瘤抑制基因，存在于CHL和PMBL中。EB病毒−中TNFAIP3基因突变频率明显高于EBV+CHL，提示TNFAIP3失活和EB病毒感染在CHL发病中的作用是互补的。
Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor κB (NF-κB). NF-κB activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus–positive (EBV+) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV− cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-κB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-κB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-κB activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV− than EBV+ cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.
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影响因子：
6
作者：
Martín-Subero, JI;Chudoba, I;Siebert, R
通讯作者：
Siebert, R
影响因子：
20.3
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