Significance and Function of HGAL in Lymphoma

描述(申请人提供)：这个项目是基于我们最近发现人类生发中心相关淋巴瘤(HGAL)的高表达是弥漫性大B细胞淋巴瘤(DLBCL)患者生存时间延长的独立预测因素。HGAL含有一个基于酪氨酸的免疫受体激活基序(ITAM)，提示其在信号转导中发挥作用。HGAL是一种IL-4诱导基因，仅在生发中心来源的淋巴瘤和生发中心淋巴细胞中高水平表达，尤其是中心母细胞，具有高增殖率和高凋亡率的特点。这些观察表明，高HGAL含量肿瘤患者的较好生存可能归因于该基因在这些过程中的特定功能。然而，我们另一个有趣的发现是，BCL6和FN1-这两个都是IL-4诱导基因也是DLBCL患者生存的独立预测因素。由于这些IL-4诱导基因的高表达与延长生存期相关，这增加了HGAL高表达可能是预测这些肿瘤良好预后的特定IL-4效应的标志。事实上，我们的初步数据表明，EL-4在肿瘤来源的高HGAL和低HGAL DLBCL细胞系中对信号、基因表达和增殖的影响不同。因此，该项目的主要目标是建立与肿瘤相关的HGAL功能，并确定HGAL的表达是否直接有利于改善DLBCL的生存，或者是IL-4对淋巴瘤影响的标志。 在这个项目中，我们将：1)。检测HGAL对细胞增殖和凋亡的影响；确定HGAL蛋白在DLBCL和其他淋巴瘤中的表达对预后和诊断的意义。确定IL-4诱导低HGAL DLBCL细胞周期停滞的机制，4)。将我们对IL-4对DLBCL细胞增殖和凋亡的影响的观察扩展到原代表达高HGAL和低HGAL的DLBCL肿瘤。这些发现将为最常见的淋巴瘤-DLBCL建立一个免疫组织化学预后标志物，并将用于临床实践，并将增加当前临床预后指标的预后能力。此外，这些研究应该确定HGAL在生发中心淋巴细胞和生发中心来源淋巴瘤中的潜在功能，以及IL-4在不同的DLBCL亚群中的潜在作用。这些机制研究可能为新的治疗策略提供方法。

DESCRIPTION (provided by applicant): This project is based on our recent finding that high expression of Human Germinal center Associated Lymphoma (HGAL) - a new gene that we recently cloned and characterized - is an independent predictor of prolonged survival of diffuse large B cell lymphoma (DLBCL) patients. HGAL contains an immunoreceptor tyrosine-based activation motif (ITAM) suggesting a function in signal transduction. HGAL is an IL-4 inducible gene expressed at high levels only in germinal center derived lymphomas and germinal center lymphocytes, especially centroblasts, characterized by high rates of proliferation and apoptosis. These observations suggest that the better survival of patients with high HGAL-content tumors may be attributed to a specific, function of this gene in these processes. However, our additional interesting finding is that BCL6 and FN1- both of which are IL-4 inducible genes are also independent predictors of DLBCL patients' survival. Since high expression of each of these IL-4 inducible genes correlates with prolonged survival, this raises the possibility that high HGAL expression may be a marker of specific IL-4 effects that predicate the good prognosis of these tumors. Indeed, our preliminary data suggest that EL-4 has different effects on signaling, gene expression and proliferation in high-HGAL versus low-HGAL DLBCL cell lines derived from tumors. Therefore the major goal of this project is to establish tumor-related HGAL function and to determine whether HGAL expression directly predisposes to improved DLBCL survival or is a marker of IL-4 effects on lymphoma. In this project we will: 1). determine effects of HGAL on cell proliferation and apoptosis, 2). determine the prognostic and diagnostic significance of HGAL protein expression in DLBCL and other lymphomas, 3). determine the mechanisms underlying cell cycle arrest induced by IL-4 in the low-HGAL DLBCL cells, 4). extend our observations on effects of IL-4 on proliferation and apoptosis of DLBCL cell lines to primary high-HGAL and Iow-HGAL expressing DLBCL tumors. These findings should establish an immunohistochemical prognostic marker for the most common type of lymphoma - DLBCL that will be used in clinical practice and will add to the prognostic power of the current clinical prognostic indexes. Furthermore, these studies should determine the potential function of HGAL in germinal center lymphocytes and germinal center derived lymphomas and the potential role of IL-4 in distinct DLBCL subsets. These mechanistic studies may provide approaches for new therapeutic strategies.