Significance and Function of HGAL in Lymphoma

描述（由申请人提供）：本项目基于我们最近的发现，即人类生殖中心相关淋巴瘤（HGAL）的高表达-我们最近克隆和表征的一种新基因-是弥漫性大B细胞淋巴瘤（DLBCL）患者生存期延长的独立预测因子。HGAL含有基于免疫受体酪氨酸的激活基序（ITAM），提示其在信号转导中的功能。HGAL是一种IL-4诱导基因，仅在生殖中心来源的淋巴瘤和生殖中心淋巴细胞中高水平表达，特别是中心母细胞，其特征在于高增殖率和凋亡率。这些观察结果表明，HGAL含量高的肿瘤患者的生存率更高可能归因于该基因在这些过程中的特定功能。然而，我们另外一个有趣的发现是，BCL 6和FN 1都是IL-4诱导基因，也是DLBCL患者生存的独立预测因子。由于这些IL-4诱导基因的高表达与延长的生存期相关，这提高了HGAL高表达可能是预测这些肿瘤的良好预后的特异性IL-4作用的标志物的可能性。事实上，我们的初步数据表明，EL-4对来自肿瘤的高HGAL与低HGAL DLBCL细胞系中的信号传导、基因表达和增殖具有不同的影响。因此，该项目的主要目标是建立肿瘤相关的HGAL功能，并确定HGAL表达是否直接倾向于改善DLBCL存活率或作为IL-4对淋巴瘤作用的标志物。 在这个项目中，我们将：1）。确定HGAL对细胞增殖和凋亡的影响，2）.确定HGAL蛋白表达在DLBCL和其他淋巴瘤中的预后和诊断意义，3）。确定在低HGAL DLBCL细胞中由IL-4诱导的细胞周期停滞的潜在机制，4）。将我们对IL-4对DLBCL细胞系的增殖和凋亡的影响的观察扩展到原发性高HGAL和低HGAL表达的DLBCL肿瘤。这些发现应该为最常见类型的淋巴瘤- DLBCL建立一个免疫组化预后标志物，该标志物将用于临床实践，并将增加当前临床预后指标的预后能力。此外，这些研究应确定HGAL在生发中心淋巴细胞和生发中心衍生的淋巴瘤中的潜在功能以及IL-4在不同DLBCL亚群中的潜在作用。这些机制的研究可能提供新的治疗策略的方法。

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.