Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling
Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling
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DOI：
10.1182/blood-2007-04-084707
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发表时间：
2008-01-01
期刊：
影响因子：
20.3
通讯作者：
Kelly, John A.
中科院分区：
文献类型：
--
作者：
Bessette, Katherine;Lang, Mark L.;Kelly, John A.
Stat5 蛋白是许多细胞因子激活的关键信号分子。在免疫系统中，Stat5 在胸腺细胞发育和 T 细胞增殖方面发挥着重要作用。 Stat5 与恶性转化有关，此外，Stat5 的活化酪氨酸磷酸化形式经常在人类淋巴瘤中观察到。我们之前证明了 Stat5 的致癌潜力，在淋巴细胞中过表达 Stat5a 或 Stat5b 的转基因 (TG) 小鼠中，很大一部分会发生胸腺淋巴母细胞淋巴瘤。此外，免疫或 T 细胞受体 (TCR) 转基因的表达增加了肿瘤形成的速度。在这里，我们通过探索主要组织相容性复合体 (MHC)/TCR 和前 TCR 信号的贡献来研究 Stat5 介导的淋巴瘤发生的机制。我们提供的数据表明，即使没有任何一种条件，Stat5b TG 小鼠也会意外地发展出 CD8(+) 淋巴瘤。事实上，Stat5b 转基因介导的淋巴瘤的加速发生在 TCR α(-/-) 和前 TCR α(-/-) 背景上。根据这些数据，我们提出了一个模型，其中双阴性/双阳性 (DN/DP) 阶段 T 细胞发育的改变与未成熟胸腺细胞中细胞因子介导的途径配合，在 Stat5b TG 小鼠中产生淋巴母细胞 T 细胞淋巴瘤。
Stat5 proteins are critical signaling molecules activated by many cytokines. Within the immune system, Stat5 plays important roles related to the development of thymocytes and proliferation of T cells. Stat5 has been implicated in malignant transformation, and moreover, the activated tyrosine phosphorylated form of Stat5 is frequently observed in human lymphomas. We previously demonstrated the oncogenic potential of Stat5, with thymic lymphoblastic lymphomas developing in a significant proportion of trans-genic (TG) mice overexpressing Stat5a or Stat5b in lymphocytes. In addition, immunization or expression of a T-cell receptor (TCR) transgene augmented the rate of tumor formation. Here, we investigate the mechanism of Stat5-mediated lymphomagenesis by exploring the contributions of major histocompatibility complex (MHC)/TCR and pre-TCR signals. We present data demonstrating that Stat5b TG mice unexpectedly develop CD8(+) lymphoma even in the absence of eithertion. Indeed, acceleration of Stat5b transgene-mediated lymphoma occurred on TCR alpha(-/-) and pre-TCR alpha(-/-) backgrounds. In light of these data, we propose a model in which alterations in T-cell development at the double-negative/double-positive (DN/DP) stages cooperate with cytokine-mediated pathways in immature thymocytes to give rise to lymphoblastic T-cell lymphomas in Stat5b TG mice.