Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.
Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.
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DOI：
10.1038/nature07968
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发表时间：
2009-06-04
期刊：
影响因子：
64.8
通讯作者：
Pasqualucci, Laura
中科院分区：
文献类型：
--
作者：
Compagno, Mara;Lim, Wei Keat;Grunn, Adina;Nandula, Subhadra V.;Brahmachary, Manisha;Shen, Qiong;Bertoni, Francesco;Ponzoni, Maurilio;Scandurra, Marta;Califano, Andrea;Bhagat, Govind;Chadburn, Amy;Dalla-Favera, Riccardo;Pasqualucci, Laura
弥漫性大B细胞淋巴瘤（DLBCL）是成年期最常见的淋巴瘤形式，包括多种生物学和临床不同的亚型，包括生发中心B细胞样（GCB）和活化B细胞样（ABC） DLBCL。基因表达谱研究表明，其最具侵袭性的亚型ABC-DLBCL与NF-kB转录复合物的组成性激活有关。然而，除了一小部分病例外，目前尚不清楚这些肿瘤中的NF-kB激活是肿瘤细胞起源的内在程序还是发病事件。在这里，我们发现50%的ABC-DLBCL和一小部分的GCB-DLBCL携带多个基因的体细胞突变，包括NF-kB的阴性（TNFAIP3/A20）和阳性（CARD11、TRAF2、TRAF5、MAP3K7/TAK1和TNFRSF11A/RANK）调节因子。其中，A20基因最常受影响，该基因编码一种泛素修饰酶，参与NF-kB反应的终止，约30%的患者因突变和/或缺失而表现出双等位基因失活。当A20重新引入携带双等位基因失活的细胞系时，A20诱导细胞凋亡和细胞生长停滞，表明其肿瘤抑制作用。不太常见的是，TRAF2和CARD11的错义突变会产生显著增强NF-kB激活能力的分子。因此，我们的研究结果表明，DLBCL中NF-kB的激活是由影响多个基因的遗传病变引起的，这些基因的丢失或激活可能通过导致NF-kB反应异常延长来促进淋巴瘤的发生。
Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB responses, is most commonly affected, with ~30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses.
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