Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma
Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma
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DOI：
10.1182/blood-2009-03-208215
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发表时间：
2009-09-10
期刊：
影响因子：
20.3
通讯作者：
Borst, Jannie
中科院分区：
文献类型：
--
作者：
Middendorp, Sabine;Xiao, Yanling;Borst, Jannie
在生发中心 (GC)，B 细胞急剧增殖并使其免疫球蛋白基因多样化，从而增加了恶性转化的风险。 GC B 细胞反应依赖于与滤泡树突状细胞 (FDC) 的串扰，FDC 上的共刺激受体 CD137 及其 GC B 细胞上的配体可能对此做出贡献。我们报告，缺乏 CD137 配体 (CD137L) 的小鼠容易患 B 细胞淋巴瘤，12 个月龄时的发病率约为 60%。淋巴瘤膜标志物是 GC B 细胞的特征。纵向组织学分析将 GC 确定为致癌转化位点，并将约 200 只小鼠中发现的 85% 的恶性肿瘤归类为 GC 衍生的 B 细胞淋巴瘤。为了描述淋巴瘤发生的机制，比较了野生型和 CD137L 缺陷型 GC B 细胞的基因表达谱。 CD137L 缺陷与有限基因集的表达增强相关，其中包括 Bcl-10 和 GC 反应调节因子 Bcl-6、Spi-B、Elf-1、Bach2 和激活诱导的胞苷脱氨酶。其中包括介导人类 GC B 细胞淋巴瘤发展的原癌基因。我们得出结论，CD137L 通常调节 GC B 细胞反应，从而起到肿瘤抑制因子的作用。 （血。2009；114：2280-2289）
In the germinal center (GC), B cells proliferate dramatically and diversify their immunoglobulin genes, which increases the risk of malignant transformation. The GC B-cell reaction relies on crosstalk with follicular dendritic cells (FDCs), to which the costimulatory receptor CD137 on FDCs and its ligand on GC B cells potentially contribute. We report that mice deficient for CD137 ligand (CD137L) are predisposed to develop B-cell lymphoma, with an incidence of approximately 60% at 12 months of age. Lymphoma membrane markers were characteristic of GC B cells. Longitudinal histologic analysis identified the GC as site of oncogenic transformation and classified 85% of the malignancies found in approximately 200 mice as GC-derived B-cell lymphoma. To delineate the mechanism underlying lymphomagenesis, gene expression profiles of wild-type and CD137L-deficient GC B cells were compared. CD137L deficiency was associated with enhanced expression of a limited gene set that included Bcl-10 and the GC response regulators Bcl-6, Spi-B, Elf-1, Bach2, and activation-induced cytidine deaminase. Among these are proto-oncogenes that mediate GC B-cell lymphoma development in humans. We conclude that CD137L ordinarily regulates the GC B-cell response and thereby acts as a tumor suppressor. (Blood. 2009; 114: 2280-2289)