Jak/STAT signaling in human T-cell lymphomas

描述(申请人提供)：这项研究的目的是通过评估人类T细胞淋巴瘤，更好地定义JAK/STAT信号异常在癌症发病机制中的作用并了解其机制和后果。大量的实验证据表明，JAK1/JAK3/STAT3/STAT5信号复合体与多种受体共有的公共g链(GC)相关，这些受体受到对正常T细胞活化和成熟至关重要的细胞因子IL-2、-4、-7、-9、-15和-21的刺激，在许多T细胞淋巴瘤的发病机制中起着核心作用。SHP-1酪氨酸磷酸酶编码基因的表观遗传沉默是细胞信号的负调控因子，有助于GC相关JAK/STAT通路的异常、持久激活。为了实现这项研究的目标，我们将审查： 1.JAK1、JAK3活化在T细胞恶性转化中的作用机制我们将集中讨论IL-15和IL-21在T细胞淋巴瘤发生中的作用，以及JAK1和JAK3在体外T细胞淋巴瘤和体内JAK3中的相对作用。 2.通过评估STATS、STAT5a和STAT5b在T细胞转化中的相对作用，探讨它们在T细胞转化中的作用。我们将重点关注这三个STATS对T细胞淋巴瘤细胞功能和基因表达的影响，以确定直接与恶性细胞表型相关的潜在效应蛋白。此外，我们还将确定STAT3诱导的表观遗传基因沉默的靶基因。 3.STAT3在SHP-1基因表观遗传沉默中的作用及机制。我们将重点介绍STAT3及其DNA甲基转移酶(DNMT)和甲基CpG结合蛋白(MBD)家族成员在SHP-1基因启动子DNA甲基化中的作用。 这项研究应该会对T细胞淋巴瘤的至少一些亚型的发病机制有更好的理解。此外，基于选择性地抑制GC相关的JAK/STAT信号转导通路中的这些元件，它可能导致淋巴瘤的新疗法，这些元件在恶性T细胞中优先利用和/或以ABABABABER方式调节。由于STAT3和STAT5的持续激活在多种恶性肿瘤中都有报道，因此这项研究的结果可能会影响对发病机制的理解，并最终影响对各种类型癌症的治疗。

DESCRIPTION (provided by applicant): The purpose of this study is to define better the role and understand the mechanisms and consequences of aberrant Jak/STAT signaling in the pathogenesis of cancer by evaluating human T-cell lymphomas. The accumulated experimental evidence indicates that the Jak1/Jak3/STAT3/STAT5 signaling complex associated with the common g chain (gc) shared by several receptors stimulated by cytokines which are critical for activation and maturation of normal T cells: IL-2, -4, -7, -9, -15, and -21, plays a central role in the pathogenesis of a large subset of T-cell lymphomas. Epigenetic silencing of the gene coding for the SHP-1 tyrosine phosphatase, a negative regulator of the cell signaling, contributes to the aberrant, persistent activation of the gc-related Jak/STAT pathways. To accomplish goals of the study we will examine: 1. mechanism and functional role of Jak1 and Jak3 activation in the malignant T-cell transformation. We will focus on the putative role of IL-15 and IL-21 in and the relative contribution of Jak1 and Jak3 to the T-cell lymphomagenesis in vitro and of Jak3 in vivo. 2. role of STATS, STAT5a and STAT5b in the T-cell transformation by evaluating their relative contributions to the lymphomagenesis. We will focus on the impact of the three STATs on the T-cell lymphoma cell function and gene expression to identify potential effector proteins directly responsible for the malignant cell phenotype. In addition, we will identify the target genes of the STAT3-induced epigenetic gene silencing. 3. role of STAT3 in and the mechanisms of the epigenetic silencing of the SHP-1 gene. We will focus on the role of STAT3 and members of the DNA methyltransferase (DNMT) and methyl CpG-binding (MBD) protein families in the DNA methylation of the SHP-1 gene promoter. This study should result in a better understanding of the pathogenesis of at least some subtypes of T-cell lymphoma. Furthermore, it may lead to novel therapy(ies) for the lymphoma based on selective inhibition of these elements of the gc-associated Jak/STAT signal transduction pathway that are preferentially utilized and/or abberantly regulated in malignant T cells. Because constant activation of STAT3 and, to lesser degree, of STAT5 has been documented in a large spectrum of malignancies, results of this study may impact on understanding pathogenesis and, ultimately, on treatment of various type of cancer.