Significance and Function of HGAL in Lymphoma

HGAL 在淋巴瘤中的意义和功能

• 批准号: 7046800
• 负责人: IZIDORE S LOSSOS
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046800
• 关键词: B cell lymphoma; apoptosis; cell line; cell proliferation; clinical research; gene expression; human subject; immunocytochemistry; interleukin 4; microarray technology; molecular oncology; neoplasm /cancer genetics; protein structure function; proteins; transcription factor

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.

描述（由申请人提供）：该项目基于我们最近的发现，即人类生发中心相关淋巴瘤 (HGAL) 的高表达（我们最近克隆和表征的新基因）是弥漫性大 B 细胞延长存活的独立预测因素淋巴瘤（DLBCL）患者。 HGAL 含有基于免疫受体酪氨酸的激活基序 (ITAM)，表明其具有信号转导功能。 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，特别是中心母细胞中高水平表达，其特征是高增殖率和高凋亡率。这些观察结果表明，高 HGAL 含量肿瘤患者的更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（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期相关，因此高 HGAL 表达可能是特定 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 对源自肿瘤的高 HGAL 与低 HGAL DLBCL 细胞系的信号传导、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与肿瘤相关的 HGAL 功能，并确定 HGAL 表达是否直接有助于改善 DLBCL 存活率，或者是 IL-4 对淋巴瘤影响的标志物。 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)。确定低 HGAL DLBCL 细胞中 IL-4 诱导细胞周期停滞的机制，4)。将我们对 IL-4 对 DLBCL 细胞系增殖和凋亡的影响的观察扩展到原发性高 HGAL 和低 HGAL 表达 DLBCL 肿瘤。这些发现应该为最常见的淋巴瘤类型——DLBCL建立一个免疫组织化学预后标志物，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淋巴瘤中的潜在功能以及 IL-4 在不同 DLBCL 亚型中的潜在作用。这些机制研究可能为新的治疗策略提供方法。