EBV LMP1/LMP2A Proteins Promote Hodgkin-like Lymphomas in Humanized Mice
EBV LMP1/LMP2A 蛋白促进人源化小鼠霍奇金样淋巴瘤的发生
基本信息
- 批准号:10152365
- 负责人:
- 金额:$ 38.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-13 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS-Related Hodgkin&aposs LymphomaAIDS-Related LymphomaAcquired Immunodeficiency SyndromeAttenuatedAutocrine CommunicationAutomobile DrivingB-Cell Antigen ReceptorB-Cell LymphomasB-LymphocytesCD4 Positive T LymphocytesCell LineCellsCollagenDDR1 geneDevelopmentEBNA2 proteinEnvironmentEpstein-Barr Virus InfectionsEpstein-Barr Virus latencyGoalsGrowthHIV InfectionsHodgkin DiseaseHumanHuman Herpesvirus 4ImmunocompetenceImmunocompromised HostImmunosuppressionIn VitroInflammatoryLMP1LaboratoriesLeadLymphomaLymphoma cellMalignant NeoplasmsMembrane ProteinsModelingPDGFA genePDGFRA geneParacrine CommunicationPathway interactionsPatientsPhenotypeProteinsReceptor Protein-Tyrosine KinasesResearchRoleSignal PathwaySignal TransductionT-LymphocyteTNFRSF5 geneTranscription CoactivatorTumor-DerivedUmbilical Cord BloodViral ProteinsVirusVirus Latencycell growthhumanized mouseimmunogenicimprovedin vitro Modelin vivoin vivo Modelinsightmouse modelmutantneoplastic cellnotch proteinnovelnovel therapeuticsoverexpressionpublic health relevancetumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Epstein-Barr virus is an important cause of AIDS-related lymphomas (ARLs) world-wide, including Hodgkin
lymphomas (HLs) that are driven by the EBV latent membrane proteins LMP1 (a CD40 mimic) and LMP2A (a
BCR mimic), in conjunction with a supportive tumor microenvironment. Although the EBV protein EBNA2 (which
mimics notch signaling) is required for EBV-induced transformation of B cells in vitro, cells that express EBNA2
have the “type III” form of viral latency, which is highly immunogenic. Thus, most EBV-infected human
lymphomas (including ARLs in cART-treated patients) do not express EBNA2. However, there is currently no in
vivo or in vitro model available to study how EBV infection can cause lymphomas in the absence of EBNA2
expression, and the only EBV+ HL cell line, L591, has switched to type III latency. Increasing evidence suggests
that HIV infection collaborates with EBV to induce lymphomas not only by inducing immunosuppression, but by
creating a pro-inflammatory microenvironment that promotes tumors with more stringent forms of EBV latency
(such as the “type II” form that occurs in HLs) that do not express EBNA2. Our lab has developed a novel cord
blood-humanized mouse model which provides a highly supportive CD4 T cell-rich environment that allows
certain EBV mutants previously considered “non-transforming” in vitro to induce lymphomas in vivo. Our new
exciting preliminary results reveal that a naturally occurring EBNA2-deleted EBV strain (P3HR1) that is
completely non-transforming in vitro causes Hodgkin-like lymphomas that express LMP1 and LMP2A in this
model. Furthermore, our preliminary results suggest that similar to human HLs, lymphomas induced by EBNA2-
deleted EBV are heavily infiltrated with collagen, express the pro-survival collagen-stimulated receptor tyrosine
kinase DDR1, and have activated PDGFRA and notch-1 signaling. Thus, we believe we have created the first in
vivo model for EBV-induced Hodgkin lymphoma. In this proposal, we will dissect the roles of the EBV proteins
LMP1 and LMP2A, as well as the tumor microenvironment, in driving lymphomas induced by EBNA2-deleted
EBV in humanized mice. We hypothesize that both LMP1 and LMP2A, as well as CD4 T cell- and collagen-
derived signals in the microenvironment, are required for the growth of these lymphomas. In Aim 1, we will
compare the phenotypes of wild-type (WT) versus EBNA2-deleted (Akata strain) EBV in humanized mouse
models, and identify paracrine and/or autocrine signaling pathways (derived from T cells, B cells and/or collagen)
that compensate for loss of EBNA2 expression both in vivo and in L591 HL cells in vitro. In Aim 2, we will define
the roles of LMP1 and LMP2A on tumor cell growth, and in regulating the tumor microenvironment, in both the
CBH model in vivo and in L591 cells in vitro. In Aim 3, we will determine whether inhibiting notch, PDGFRA
and/or DDR1 signaling attenuates the growth of lymphomas induced by WT virus and/or EBNA2-deleted virus
in humanized mice or in L591 cells in vitro. The results of these studies should provide key insights into the
mechanism(s) by which LMP1 and LMP2A promote AIDS-related Hodgkin lymphomas, and elucidate how the
tumor microenvironment cooperates with type II latent EBV infection to induce human lymphomas in vivo when
EBNA2 expression is shut off.
项目总结/文摘
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Shannon Celeste Kenney其他文献
Shannon Celeste Kenney的其他文献
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{{ truncateString('Shannon Celeste Kenney', 18)}}的其他基金
Roles of LMP1 and MYC in EBV-induced B-cell tumors
LMP1 和 MYC 在 EBV 诱导的 B 细胞肿瘤中的作用
- 批准号:
10749776 - 财政年份:2023
- 资助金额:
$ 38.15万 - 项目类别:
Project 5 - EBV Drivers of Oncogenesis and Novel Therapies
项目 5 - 肿瘤发生的 EBV 驱动因素和新疗法
- 批准号:
10910339 - 财政年份:2023
- 资助金额:
$ 38.15万 - 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
- 批准号:
10428543 - 财政年份:2019
- 资助金额:
$ 38.15万 - 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
- 批准号:
9891040 - 财政年份:2019
- 资助金额:
$ 38.15万 - 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
- 批准号:
10667423 - 财政年份:2019
- 资助金额:
$ 38.15万 - 项目类别:
Role of EBV Lytic Infection in Viral Tumorigenesis
EBV 裂解性感染在病毒肿瘤发生中的作用
- 批准号:
10190848 - 财政年份:2019
- 资助金额:
$ 38.15万 - 项目类别:
EBV LMP1/LMP2A Proteins Promote Hodgkin-like Lymphomas in Humanized Mice
EBV LMP1/LMP2A 蛋白促进人源化小鼠霍奇金样淋巴瘤的发生
- 批准号:
10403940 - 财政年份:2018
- 资助金额:
$ 38.15万 - 项目类别:
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