VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia
VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia
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DOI：
10.1182/blood-2003-07-2469
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发表时间：
2004-03-15
期刊：
影响因子：
20.3
通讯作者：
Cory, S
中科院分区：
文献类型：
--
作者：
Egle, A;Harris, AW;Cory, S
在人类滤泡性淋巴瘤中，t(14；18)染色体易位通过将抗凋亡癌基因bcl2连接到免疫球蛋白重链(IgH)基因来激活该基因。由IgH增强子(Emu)控制的表达Bcl2的转基因小鼠不会患滤泡性淋巴瘤，尽管它们确实增加了其他B淋巴样肿瘤的发病率。我们现在已经分析了携带受Vav基因调控序列(VavP)控制的Bcl2转基因小鼠的肿瘤发生，VavP在多个造血系中进行表达。与Emu-Bcl2小鼠不同，许多10个月大的VavP-Bcl2小鼠患上滤泡性淋巴瘤。年轻的VavP-Bcl2小鼠具有过多的生发中心扩大和经历了IgH类转换和V基因超突变的循环B细胞数量的大幅增加。VavP-Bcl2小鼠的外周T细胞隔室比Emu-Bcl2小鼠大，值得注意的是，CD4T细胞比正常小鼠增加了5倍。生发中心的增生需要CD4T细胞，因为它可以被体内的抗CD4抗体消除。VavP-Bcl2小鼠也有患自身免疫型肾脏疾病的倾向。我们认为，B和T细胞生存能力的提高促进了生发中心反应的延长，而自身反应和高度突变共同导致滤泡性淋巴瘤。(C)2004年，由美国血液病学会提供。
In human follicular lymphoma the t(14; 18) chromosome translocation activates the antiapoptotic oncogene Bcl2 by linking it to the immunoglobulin heavy chain (IGH) locus. Transgenic mice expressing Bcl2 controlled by an Igh enhancer (Emu) do not develop follicular lymphoma, although they do have an increased incidence of other B-lymphoid neoplasms. We have now analyzed tumorigenesis in mice bearing a Bcl2 transgene controlled by Vav gene regulatory sequences (VavP), which confer expression in multiple hematopoietic lineages. Unlike Emu-Bcl2 mice, many VavP-Bcl2 mice older than 10 months developed follicular lymphoma. Young VavP-Bcl2 mice had an overabundance of enlarged germinal centers and greatly elevated numbers of cycling B cells that had undergone IgH class switching and V-gene hypermutation. The peripheral T-cell compartment was larger in the VavP-Bcl2 mice than in Emu-Bcl2 strains and, notably, CD4 T cells were 5-fold increased over normal. The germinal center hyperplasia required CD4 T cells, because it could be abolished by anti-CD4 antibody in vivo. VavP-Bcl2 mice also had a propensity to develop kidney disease of the autoimmune type. We suggest that the increased survival capacity of B and T cells fosters prolonged germinal center reactions, and that autoreactivity and hypermutation conspire to generate follicular lymphoma. (C) 2004 by The American Society of Hematology.