Inhibition of caspase-8 activity caused by overexpression of bcl10 contributes to the pathogenesis of high-grade MALT lymphoma
Inhibition of caspase-8 activity caused by overexpression of bcl10 contributes to the pathogenesis of high-grade MALT lymphoma
复制标题
bcl10过度表达引起的caspase-8活性抑制有助于高级别MALT淋巴瘤的发病机制
DOI：
10.1002/pbc.23331
复制
发表时间：
2012-06-01
影响因子：
3.2
通讯作者：
Zhang, Quangeng
中科院分区：
文献类型：
--
作者：
Chen, Yan;Yang, Yishu;Zhang, Quangeng
粘膜相关淋巴组织淋巴瘤（MALT）约占所有非霍奇金淋巴瘤的8%，是胃肠道中最常见的淋巴瘤。它由基因异常或细菌感染/慢性炎症引起。b细胞淋巴瘤/白血病10 （BCL10）过表达和核表达与具有遗传异常的高级MALT淋巴瘤相关，这些淋巴瘤对幽门螺杆菌根除治疗无反应。为了探索BCL10过表达在MALT淋巴瘤发病机制和恶性表型中的分子机制，我们培育了E mu SR-BCL10转基因小鼠。过程。通过产生杂合子和纯合子EuSR-BCL10小鼠，并显示BCL10在这些小鼠中的表达水平，我们定量地检测了MZ B细胞扩增和抑制caspase-8活性与BCL10蛋白水平的关系。我们还通过Western blot检测了API2和caspase-8的表达，并通过共免疫沉淀检测了它们与BCL10的相互作用。结果。MZ b细胞扩增与BCL10蛋白水平呈剂量依赖性直接相关。随着BCL10蛋白水平的升高，caspase- 8和-3活性受到抑制，caspase-9活性不受抑制。扩增后的MZ B细胞在抗免疫球蛋白M刺激下表现出选择性存活，而在地塞米松、g辐射或抗cd95刺激下则不表现出选择性存活，提示过表达的BCL10通过B细胞抗原受体（BCR）途径发挥抗凋亡作用。过表达的BCL10蛋白与caspase-8和API2蛋白共免疫沉淀，提示它们在体内相互作用。结论。我们的数据证明了BCL10过表达在高级别MALT淋巴瘤发病机制中的新作用，通过增加API2的表达，然后与BCL10/caspase-8形成蛋白复合物，导致caspase-8活性抑制。儿科血癌杂志2012；58:865-871。(C) 2011 Wiley期刊公司
Background Mucosa-associated lymphoid tissue (MALT) lymphoma comprises approximately 8% of all non-Hodgkin lymphomas and is the most common lymphoma in the gastro-intestinal tract. It is caused by genetic abnormalities or bacterial infections/chronic inflammation. B-cell lymphoma/leukemia 10 (BCL10) overexpression and nuclear expression have been associated with high-grade MALT lymphomas with genetic abnormalities that are unresponsive to Helicobacter pylori eradication treatment. To explore the molecular mechanism of BCL10 overexpression on the pathogenesis and malignant phenotype of MALT lymphoma, we generated E mu SR-BCL10 transgenic mice. Procedure. By generation of heterozygous and homozygous EuSR-BCL10 mice and showing BCL10 expression levels in these mice, we quantitatively examined relation of MZ B cell expansion and inhibition of caspase-8 activity with BCL10 protein level. We also investigated API2 and caspase-8 expression by Western blot and their interaction with BCL10 by co-immunoprecipitation. Results. MZ B-cell expansion is directly related to BCL10 protein level in a dose-dependent manner. The activity of caspases-8 and -3, but not caspase-9, was inhibited with increasing of BCL10 protein level. Expanded MZ B cells showed selective survival under stimulation of anti-immunoglobulin M, but not dexamethasone, g-irradiation, or anti-CD95, implying that overexpressed BCL10 exerts anti-apoptotic effects through B-cell antigen receptor (BCR) pathway. Overexpressed BCL10 protein co-immunoprecipitated with caspase-8 and API2 protein, suggesting an in vivo interaction of them. Conclusion. Our data demonstrate a novel effect of overexpressed BCL10 in the pathogenesis of high-grade MALT lymphoma by increasing expression of API2 and it then forming a protein complex with BCL10/caspase-8 leading to caspase-8 activity suppression. Pediatr Blood Cancer 2012;58:865-871. (C) 2011 Wiley Periodicals, Inc.