Significance and Function of HGAL in Lymphoma

项目总结/摘要 本项目是基于我们的研究发现，高表达的人生殖中心相关淋巴瘤， （HGAL）-我们克隆和鉴定的一个新基因-是一个独立的预测因子， 弥漫性大B细胞淋巴瘤（DLBCL）和霍奇金病（HD）患者。最近，我们证明， HGAL介导IL-6诱导的对生发中心（GC）B细胞迁移的抑制。我们证明了IL-6 诱导HGAL C-末端酪氨酸的Lyn-mediated磷酸化，并导致HGAL重新定位， 足状结构和穗状丝状伪足。我们发现内源性HGAL和 肌球蛋白II和描绘的HGAL结构域负责的相互作用。我们提供的证据表明HGAL 磷酸化导致与肌球蛋白II的相互作用增加，并证明敲低 内源性HGAL改善IL-6对细胞迁移的抑制作用。综合来看，这些结果 HGAL作为IL-6对淋巴细胞迁移作用的生理介质， GC衍生淋巴瘤中的表达可能会限制肿瘤扩散并倾向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着进展， HGAL介导的细胞迁移抑制和随之而来的更好的临床结果的倾向， 表达HGAL的肿瘤目前是未知的。我们的初步数据表明，HGAL可能影响细胞 通过与肌球蛋白II相互作用和/或通过增加罗阿活性来增强运动性。然而，这些影响必须 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Rho GT3家族成员- RhoA蛋白及其效应物的影响; 3）确定 HGAL肉豆蔻酰化和棕榈酰化在其对细胞运动性的抑制作用中的作用;以及4）确定 HGAL在转基因小鼠模型中的表达对淋巴细胞分化、成熟、运动和增殖的影响 淋巴瘤形成这些研究将扩大我们对GC淋巴细胞生物学的了解， 强调淋巴细胞运动和迁移。此外，这些研究将揭示潜在的新的 调节淋巴肿瘤扩散和进展的机制。这些机制研究可能 为新的治疗方法提供了新的途径。

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.