Jak/STAT signaling in human T-cell lymphomas

描述（由申请方提供）：本研究的目的是通过评价人T细胞淋巴瘤，更好地确定异常Jak/STAT信号传导在癌症发病机制中的作用，并了解其机制和后果。积累的实验证据表明，Jak 1/Jak 3/STAT 3/STAT 5信号传导复合物与由细胞因子刺激的几种受体共享的共同g链（gc）相关，这些细胞因子对正常T细胞的活化和成熟至关重要：IL-2、-4、-7、-9、-15和-21，在大的T细胞淋巴瘤亚群的发病机制中起核心作用。编码SHP-1酪氨酸磷酸酶（细胞信号传导的负调节因子）的基因的表观遗传沉默有助于GC相关Jak/STAT途径的异常、持续激活。为了实现本研究的目标，我们将研究： 1. Jak 1和Jak 3活化在恶性T细胞转化中的机制和功能作用。我们将集中在IL-15和IL-21的推定作用，以及Jak 1和Jak 3的相对贡献，T细胞淋巴瘤在体外和Jak 3在体内。 2.通过评估STATs、STAT 5a和STAT 5 b在淋巴瘤发生中的相对贡献，来确定STATs、STAT 5a和STAT 5 b在T细胞转化中的作用。我们将重点关注三种STAT对T细胞淋巴瘤细胞功能和基因表达的影响，以确定直接负责恶性细胞表型的潜在效应蛋白。此外，我们将确定STAT 3诱导的表观遗传基因沉默的靶基因。 3. STAT 3在SHP-1基因表观遗传沉默中的作用及其机制。我们将重点关注STAT 3和DNA甲基转移酶（DNMT）和甲基CpG结合（MBD）蛋白家族成员在SHP-1基因启动子DNA甲基化中的作用。 这项研究应导致更好地了解至少一些亚型的T细胞淋巴瘤的发病机制。此外，它可能导致基于选择性抑制在恶性T细胞中优先利用和/或异常调节的GC相关Jak/STAT信号转导途径的这些元件的淋巴瘤的新疗法。由于STAT 3和STAT 5（在较小程度上）的持续激活已在大范围的恶性肿瘤中得到证实，因此本研究的结果可能会影响对发病机制的理解，并最终影响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.