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NOD.Stat5b 转基因小鼠中的增强型 T 细胞淋巴瘤是由 CD8+ 胸腺细胞中 Stat5b 的过度激活引起的。

Enhanced T cell lymphoma in NOD.Stat5b transgenic mice is caused by hyperactivation of Stat5b in CD8+ thymocytes.

机构信息

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.

出版信息

PLoS One. 2013;8(2):e56600. doi: 10.1371/journal.pone.0056600. Epub 2013 Feb 14.

DOI:10.1371/journal.pone.0056600
PMID:23457589
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3572980/
Abstract

Activation of signal transducers and activators of transcription (STAT) proteins may be critical to their oncogenic functions as demonstrated by the development of B-cell lymphoma/leukemia in transgenic (TG) mice overexpressing a constitutively activated form of Stat5b. However, low incidence of CD8(+) T cell lymphoma was observed in B6 transgenic mice overexpressing a wild-type Stat5b (B6.Stat5b(Tg)) despite of undetectable Stat5b phosphorylation and the rate of lymphomagenesis was markedly enhanced by immunization or the introduction of TCR transgenes [1]. Here, we report that the wild-type Stat5b transgene leads to the acceleration and high incidence (74%) of CD8(+) T cell lymphoblastic lymphomas in the non-obese-diabetic (NOD) background. In contrast to the B6.Stat5b(Tg) mice, Stat5b in transgenic NOD (NOD.Stat5b(Tg)) mice is selectively and progressively phosphorylated in CD8(+) thymocytes. Stat5 phosphorylation also leads to up-regulation of many genes putatively relevant to tumorigenesis. Treatment of NOD.Stat5b(Tg) mice with cancer chemopreventive agents Apigenin and Xanthohumol efficiently blocked lymphomagenesis through reduction of Stat5 phosphorylation and genes up-regulated in the NOD.Stat5b(Tg) mice. These results suggest that NOD genetic background is critical to the Stat5b-mediated lymphomagenesis through regulation of Stat5 hyperactivation. NOD.Stat5b(Tg) mouse is an excellent model for studying the molecular mechanisms underlying lymphomagenesis and testing novel chemoprevention strategies.

摘要

信号转导子和转录激活子（STAT）蛋白的激活可能对其致癌功能至关重要，这一点已被证明，即在过表达组成性激活形式的 Stat5b 的转基因（TG）小鼠中会发展出 B 细胞淋巴瘤/白血病。然而，尽管未检测到 Stat5b 磷酸化，但在过表达野生型 Stat5b 的 B6 转基因小鼠（B6.Stat5b(Tg)）中观察到 CD8(+) T 细胞淋巴瘤的发病率较低，并且通过免疫接种或引入 TCR 转基因可显著增强淋巴瘤的发生[1]。在这里，我们报告称，野生型 Stat5b 转基因导致非肥胖型糖尿病（NOD）背景下 CD8(+) T 细胞淋巴母细胞性淋巴瘤的加速和高发生率（74%）。与 B6.Stat5b(Tg) 小鼠相反，转基因 NOD（NOD.Stat5b(Tg)）小鼠中的 Stat5b 可在 CD8(+) 胸腺细胞中选择性和进行性地磷酸化。Stat5 磷酸化还导致许多被认为与肿瘤发生相关的基因上调。用癌症化学预防剂芹菜素和黄腐醇治疗 NOD.Stat5b(Tg) 小鼠可通过降低 Stat5 磷酸化和 NOD.Stat5b(Tg) 小鼠中上调的基因来有效阻止淋巴瘤的发生。这些结果表明，NOD 遗传背景通过调节 Stat5 的过度激活对 Stat5b 介导的淋巴瘤发生至关重要。NOD.Stat5b(Tg) 小鼠是研究淋巴瘤发生分子机制和测试新型化学预防策略的理想模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/aefa25628f0b/pone.0056600.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/220db60b6a92/pone.0056600.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/0872558d1c56/pone.0056600.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/9f21f8e296a9/pone.0056600.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/258a06e3b989/pone.0056600.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/aefa25628f0b/pone.0056600.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/220db60b6a92/pone.0056600.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/0872558d1c56/pone.0056600.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/9f21f8e296a9/pone.0056600.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/258a06e3b989/pone.0056600.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a94e/3572980/aefa25628f0b/pone.0056600.g005.jpg

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