Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation.
Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation.
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DOI：
10.1158/0008-5472.can-09-1110
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发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
MacLennan AJ
中科院分区：
文献类型：
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作者：
Cattoretti G;Mandelbaum J;Lee N;Chaves AH;Mahler AM;Chadburn A;Dalla-Favera R;Pasqualucci L;MacLennan AJ
S1P2鞘氨醇1-磷酸受体信号可以调控多种细胞类型的增殖、存活、形态和迁移。在这里，我们报告了S1P2−/−小鼠随着年龄的增长而发展成克隆B细胞淋巴瘤，因此大约一半的动物在1.5至2岁时表现出这种肿瘤。组织学、免疫表型和分子分析显示肿瘤具有生发中心（GC）源性弥漫性大B细胞淋巴瘤（DLBCL）的特征。肿瘤形成之前，GC B细胞和CD69+ T细胞的增加，以及自发GC形成的增加，表明S1P2缺失可能部分通过破坏GC B细胞的稳态来促进淋巴瘤发生。除了罕见的肺肿瘤外，S1P2基因破坏的影响明显局限于DLBCL。在人类中，发现28/106（26%）的DLBCL样本在S1P2基因的5 '序列中存在多个体细胞突变。突变表现出类似于IgV相关体细胞超突变机制产生的特征，但在正常GC B细胞中未检测到显著水平，这表明与肿瘤相关的异常功能。总的来说，我们的数据表明，S1P2信号可能在体内抑制DLBCL的形成中发挥关键作用。S1P2 - / -小鼠中DLBCL的高发病率，其在老年发病，以及相对缺乏其他肿瘤，使这些小鼠成为这种高度流行和侵袭性人类恶性肿瘤的新型和潜在有价值的模型。
S1P2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology and migration in many cell types in vitro. Here we report that S1P2−/− mice develop clonal B cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC) derived diffuse large B cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69+ T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P2 loss may promote lymphomagenesis in part by disrupting GC B cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P2 gene disruption is remarkably restricted to DLBCL. In humans, 28/106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5′ sequences of the S1P2 gene. Mutations displayed features resembling those generated by the IgV associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P2−/− mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy.