COBRE: DMS: STAT5: ROLE IN CTL DEVELOPMENT AND ONCOGENESIS

COBRE：DMS：STAT5：在 CTL 发育和肿瘤发生中的作用

• 批准号: 7381265
• 负责人: John A Kelly
• 金额: $ 17.01万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381265
• 关键词: lymphoma; role

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lymphoma has the second fastest growing incidence of cancer in America (behind melanoma), with a two-fold rise in incidence (8/100,000 to 16/100,000) between 1973 and 1995. Approximately 500,000 people in the United States are living with lymphoma, and 60,000 Americans are diagnosed each year, with a 50% mortality rate. T-acute lymphoblastic leukemias (T-ALLs) and lymphomas correspond to a heterogenous group of lymphoid malignancies arrested at various stages of development that largely reproduce normal thymic development. In this regard, activation of particular oncogenes has been linked to defined stages of normal development. We recently described an important role for signal transducer and activator of transcription (STAT) 5 in peripheral CD8+ T-cell homeostasis, and provided direct evidence for Stat5 as an oncogene by demonstrating that a significant proportion of mice transgenically expressing a wild type (WT) form of Stat5a or Stat5b develop thymic lymphoblastic lymphoma. Coexpression of a T-cell receptor (TCR) transgene greatly augments thymic CD8+ T-cell development in the Stat5b transgenic (TG) mice, and predisposes these Stat5b/TCR double transgenic mice to lymphoma at a much younger age than Stat5b TG mice without the TCR transgene. The fact that Stat5b TG mice coexpressing a class II restricted TCR transgene paradoxically develop CD8+ T-cell expansion and CD8+ lymphoma, is consistent with a unique effect of Stat5 overexpression on selection events within the thymus. The effect of Stat5 on the outcome of TCR/Major Histocompatability Complex (MHC) interactions could occur directly by altering downstream pathway activation (an effect of Stat5 on TCR signaling), or indirectly by influencing the population of immature thymocytes available for selection (a purely cytokine effect). Our goal is to identify the steps in normal lymphocyte development that are dramatically altered by Stat5 overexpression, and as a result favor development of CD8+ T-cells and lymphoblastic lymphomas. Specifically, we plan to determine whether Stat5 contributes to early thymocyte proliferation and survival (IL-7-dependent and independent), and/or whether Stat5 levels influence positive or negative selection (mediated by TCR/MHC interactions) (Aim 1). In addition, the signaling events by which Stat5 exerts its effect will be examined. In this regard, we plan to quantify the effect of Stat5 levels on responses to both cytokine and TCR activation by measuring Stat5 phosphorylation and downstream effects such as transcription of Stat5-dependent genes. We also wish to evaluate the factors driving lymphomagenesis by determining the critical need for cytokines and MHC interaction in this process. Finally, we want to utilize our unique lymphoma model to identify novel therapeutic targets. Collectively, these studies will more precisely identify those specific steps in T-cell development and lineage commitment in which Stat5 contributes, and where overexpression of Stat5 results in significant changes that ultimately lead to lymphomas. Exploring the role of Stat5 in T-cell development, as well as the factors contributing to Stat5-mediated lymphoma, should help elucidate the pathogenesis of lymphoma and identify targets for novel molecular therapies that could then be tested in our lymphoma model.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在美国，淋巴瘤是癌症发病率增长第二快的疾病（仅次于黑色素瘤），在1973年至1995年间发病率增长了两倍（8/100，000至16/100，000）。美国约有50万人患有淋巴瘤，每年有6万美国人被诊断出患有淋巴瘤，死亡率为50%。T-急性淋巴细胞白血病（T-ALL）和淋巴瘤对应于一组异质性淋巴恶性肿瘤，在不同的发展阶段，主要重现正常的胸腺发育。在这方面，特定致癌基因的激活与正常发育的确定阶段有关。 我们最近描述了信号转导和转录激活因子（STAT）5在外周CD 8 + T细胞稳态中的重要作用，并通过证明转基因表达野生型（WT）形式的Stat 5a或Stat 5 b的小鼠中有很大比例发生胸腺淋巴母细胞性淋巴瘤，为Stat 5作为癌基因提供了直接证据。共表达的T细胞受体（TCR）转基因大大增加了胸腺CD 8 + T细胞的发展，在Stat 5 b转基因（TG）小鼠，并倾向于这些Stat 5 b/TCR双转基因小鼠淋巴瘤在一个更年轻的年龄比Stat 5 b TG小鼠没有TCR转基因。共表达II类限制性TCR转基因的Stat 5 b TG小鼠矛盾地发展CD 8 + T细胞扩增和CD 8+淋巴瘤的事实与Stat 5过表达对胸腺内选择事件的独特作用一致。Stat 5对TCR/主要组织相容性复合物（MHC）相互作用的结果的影响可以通过改变下游途径活化（Stat 5对TCR信号传导的影响）直接发生，或通过影响可用于选择的未成熟胸腺细胞的群体（纯粹的细胞因子效应）间接发生。 我们的目标是确定正常淋巴细胞发育中的步骤，这些步骤被Stat 5过表达显著改变，从而有利于CD 8 + T细胞和淋巴母细胞性淋巴瘤的发展。具体而言，我们计划确定Stat 5是否有助于早期胸腺细胞增殖和存活（IL-7依赖性和非依赖性），和/或Stat 5水平是否影响阳性或阴性选择（由TCR/MHC相互作用介导）（目的1）。此外，将检查Stat 5发挥其作用的信号事件。在这方面，我们计划通过测量Stat 5磷酸化和下游效应（如Stat 5依赖性基因的转录）来量化Stat 5水平对细胞因子和TCR活化反应的影响。我们还希望通过确定在这个过程中细胞因子和MHC相互作用的关键需求来评估驱动淋巴瘤发生的因素。最后，我们希望利用我们独特的淋巴瘤模型来确定新的治疗靶点。 总的来说，这些研究将更精确地确定Stat 5参与的T细胞发育和谱系定型中的那些特定步骤，以及Stat 5的过度表达导致最终导致淋巴瘤的显著变化。探索Stat 5在T细胞发育中的作用，以及促成Stat 5介导的淋巴瘤的因素，应该有助于阐明淋巴瘤的发病机制，并确定新的分子疗法的靶点，然后可以在我们的淋巴瘤模型中进行测试。