Significance and Function of HGAL in Lymphoma

项目摘要/摘要 这个项目是基于我们的发现，人类生发中心相关淋巴瘤的高表达 (HGAL)--我们克隆并鉴定的一种新基因--是一种独立的预测长寿的指标 弥漫性大B细胞淋巴瘤(DLBCL)和霍奇金病(HD)患者。最近，我们展示了 HGAL介导IL-6抑制生发中心(GC)B细胞迁移。我们证明了IL-6 诱导Lyn介导的HGAL C末端酪氨酸的磷酸化，并导致HGAL重新定位到 足体状结构和穗状丝状足孔。我们展示了内源性HGAL和HGAL之间的相互作用 肌球蛋白II和描绘的HGAL结构域负责相互作用。我们提供了HGAL的证据 磷酸化导致与肌球蛋白II的相互作用增加，并证明了 内源性HGAL可改善IL-6对细胞迁移的抑制作用。综合来看，这些结果 HGAL是IL-6影响淋巴细胞迁移的生理介质，提示HGAL 在GC来源的淋巴瘤中的表达可能限制肿瘤的扩散，并易于获得更好的临床结果。 然而，尽管在确定HGAL在细胞过程中的作用方面取得了显著进展，但其确切的机制 HGAL介导的抑制细胞迁移和随之而来的改善临床结果的易感性 表达HGAL的肿瘤目前尚不清楚。我们的初步数据显示HGAL可能会影响细胞 通过与肌球蛋白II相互作用和/或通过增加RoA活性来运动。然而，这些影响需要 进一步调查。在这个项目中，我们将：1)确定HGAL对肌球蛋白II功能的影响；2)确定 HGAL对小分子Rho GTP酶家族成员--RhoA蛋白及其效应因子的影响 HGAL肉豆蔻酰化和棕榈酰化在其抑制细胞运动中的作用；以及4)确定 转基因小鼠模型中HGAL的表达对淋巴细胞分化、成熟、活力和免疫功能的影响 淋巴肿大。这些研究将扩大我们对GC淋巴细胞生物学的了解，具有特定的 强调淋巴细胞的运动和迁移。此外，这些研究将揭示潜在的新的 淋巴系肿瘤扩散和发展的调控机制。这些机械论的研究可能 为新的治疗提供新的方法。

Project Summary/Abstract This project is based on our findings that high expression of Human Germinal center Associated Lymphoma (HGAL) - a new gene that we cloned and characterized - is an independent predictor of prolonged survival of diffuse large B cell lymphoma (DLBCL) and Hodgkin's disease (HD) patients. Recently, we demonstrated that HGAL mediates IL-6-induced inhibition of germinal center (GC) B-cell migration. We demonstrated that IL-6 induces Lyn-mediated phosphorylation of the HGAL C-terminal tyrosine and causes HGAL relocalization to podosome-like structures and spike-like filopodia. We showed interactions between endogenous HGAL and myosin II and delineated HGAL domains responsible for the interaction. We provided evidence that HGAL phosphorylation results in increased interaction with the myosin II and demonstrated that knockdown of endogenous HGAL ameliorates the inhibitory effects of the IL-6 on cell migration. Taken together, these results identified HGAL as a physiological mediator of IL-6 effects on lymphocyte migration and suggest that HGAL expression in GC-derived lymphomas may limit tumor dissemination and predispose to better clinical outcome. However, despite the marked progress in identifying HGAL role in cellular processes, the precise mechanisms of HGAL-mediated inhibition of cell migration and consequent predisposition to better clinical outcome of tumors expressing HGAL are presently unknown. Our preliminary data demonstrates that HGAL may affect cell motility by interacting with myosin II and/or by increasing RoA activity. However, these effects need to be further investigated. In this project we will: 1) Determine effects of HGAL on myosin II function; 2) Determine effects of HGAL on a member of the small Rho GTPase family - RhoA protein and its effectors; 3) Determine the role of HGAL myristoylation and palmytoylation on its inhibitory effects on cell motility; and 4) Determine the effects of HGAL expression in transgenic mice model on lymphocyte differentiation, maturation, motility and lymphomagenesis. These studies will expand our knowledge on biology of the GC lymphocytes, with specific emphasis on lymphocyte motility and migration. Furthermore, these studies will reveal potentially new mechanisms regulating dissemination and progression of lymphoid tumors. These mechanistic studies may provide novel approaches for new therapeutic.