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，人类生发中心相关淋巴瘤（HGAL）的高表达-我们最近克隆并表征的新基因-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含有免疫受体酪氨酸激活基序（ITAM），提示其在信号转导中起作用。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，特别是成中心细胞中高水平表达，其特点是高增殖和高凋亡率。这些观察结果表明，高hgal含量肿瘤患者更好的生存率可能归因于该基因在这些过程中的特定功能。然而，我们的另一个有趣的发现是，BCL6和FN1——两者都是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生存相关，这就提出了高HGAL表达可能是特异性IL-4效应的标志，预示着这些肿瘤的良好预后。事实上，我们的初步数据表明，EL-4对肿瘤来源的高hgal和低hgal DLBCL细胞系的信号传导、基因表达和增殖有不同的影响。因此，本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的生存，或者是IL-4对淋巴瘤作用的标志。

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.