Significance and Function of HGAL in Lymphoma

HGAL 在淋巴瘤中的意义和功能

• 批准号: 8463466
• 负责人: IZIDORE S LOSSOS
• 金额: $ 22.86万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463466
• 关键词: Actins; Actomyosin; Affect; Antigens; Atypical lymphocyte; B-Cell Lymphoma 6 Protein; B-Lymphocytes; Behavior; Binding; Biological; Biological Process; Biology; C-terminal; Cell Communication; Cell Differentiation process; Cell Migration Inhibition function; Cell physiology; Cells; Characteristics; Clinical; Cloning; Complex; Cytoskeleton; Data; Development; Diagnosis; Disease; Environment; Expressed Sequence Tags; Family; Filopodia; Funding; Gene Expression Profiling; Genes; Goals; Grant; Histocompatibility Antigens Class II; Hodgkin Disease; Human; Immune response; Interleukin-6; Knowledge; Laboratories; Lead; Lymphocyte; Lymphocyte Biology; Lymphoma; Lymphomagenesis; Malignant - descriptor; Mediating; Mediator of activation protein; Molecular; Molecular Target; Motor; Myosin ATPase; Myosin Regulatory Light Chains; Myosin Type II; N-terminal; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Outcome; Pathogenesis; Pathologic Processes; Patients; Phosphorylation; Physiological; Physiological Processes; Play; Predisposition; Process; Prognostic Marker; Proteins; Reaction; Reagent; Regulation; Research; Role; Site; Structure; Structure of germinal center of lymph node; Testing; Time; Tissues; Transgenic Mice; Tumor Immunity; Tyrosine; Wound Healing; abstracting; angiogenesis; base; cancer therapy; cell mediated immune response; cell motility; gene cloning; improved; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; lymphoid neoplasm; malignant lymphocyte; member; migration; mouse model; myristoylation; neoplastic cell; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; prevent; response; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; tool; treatment strategy; tumor

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.

项目总结/文摘

项目成果

Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma.

• DOI: 10.1002/ajh.23996
• 发表时间: 2015-06
• 期刊: AMERICAN JOURNAL OF HEMATOLOGY
• 影响因子: 12.8
• 作者: Hosein, Peter J.;Sandoval-Sus, Jose D.;Goodman, Deborah;Arteaga, Alexandra Gomez;Reis, Isildinha;Hoffman, James;Stefanovic, Alexandra;Rosenblatt, Joseph D.;Lossos, Izidore S.
• 通讯作者: Lossos, Izidore S.

Biased immunoglobulin light chain use in the Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas.

偏向免疫球蛋白轻链在鹦鹉热衣原体阴性眼附件边缘区淋巴瘤中的应用。

• DOI: 10.1002/ajh.23416
• 发表时间: 2013
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Zhu,Daxing;Lossos,Chen;Chapman-Fredricks,JenniferR;Lossos,IzidoreS
• 通讯作者: Lossos,IzidoreS

Molecular and genomic aberrations in Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas.

鹦鹉热衣原体阴性眼附件边缘区淋巴瘤的分子和基因组畸变。

• DOI: 10.1002/ajh.23490
• 发表时间: 2013
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Zhu,Daxing;Ikpatt,OffiongF;Dubovy,SanderR;Lossos,Chen;Natkunam,Yasodha;Chapman-Fredricks,JenniferR;Fan,Yao-Shan;Lossos,IzidoreS
• 通讯作者: Lossos,IzidoreS

The age of the target cell affects B-cell leukaemia malignancy.

• DOI: 10.18632/aging.100244
• 发表时间: 2010-12
• 期刊: Aging
• 作者: Vicente-Dueñas C;Abollo-Jiménez F;Ruiz-Roca L;Alonso-Escudero E;Jiménez R;Cenador MB;Criado FJ;Cobaleda C;Sánchez-García I
• 通讯作者: Sánchez-García I

Genetic background affects susceptibility to tumoral stem cell reprogramming.

• DOI: 10.4161/cc.25544
• 发表时间: 2013-08-01
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: García-Ramírez I;Ruiz-Roca L;Martín-Lorenzo A;Blanco O;García-Cenador MB;García-Criado FJ;Vicente-Dueñas C;Sánchez-García I
• 通讯作者: Sánchez-García I