Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis
剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用
基本信息
- 批准号:10459337
- 负责人:
- 金额:$ 64.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-14 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAfricaAfrican Burkitt&aposs lymphomaAntigensAreaAutomobile DrivingB Cell ProliferationB-Cell ActivationB-Cell Antigen ReceptorB-Cell DevelopmentB-Cell LymphomasB-LymphocytesC-Myc TranslocationCD8-Positive T-LymphocytesCell LineCell SurvivalCell surfaceCellsCharacteristicsChildChild SupportChromatinChronicClinicalCoupledDataEBNA2 proteinEpidemiologyEpstein-Barr Virus InfectionsEpstein-Barr Virus latencyEventExposure toGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHeavy-Chain ImmunoglobulinsHuman Herpesvirus 4IGH@ gene clusterImmuneImmune responseImmune systemImmunityImmunologic SurveillanceImmunosuppressionIn VitroIndividualInfectionLarge-Cell Immunoblastic LymphomaLiteratureLymphoma cellLymphomagenesisMYC geneMaintenanceMalariaMalignant Childhood NeoplasmMediatingMolecularOncogenesParasitesPathogenesisPatternPlasmodium falciparumPublishingReceptor SignalingRegulationRiskRoleSignal TransductionSpecificitySurfaceSurface ImmunoglobulinsT-LymphocyteT-Lymphocyte SubsetsTestingTumor ImmunityViralViral GenomeVirusWorkactivation-induced cytidine deaminasec-myc Genescell transformationco-infectionhuman pathogenhumanized mousein vivoinfected B cellinterestmouse modelneoantigensneoplastic cellnovelpathogenpost-transplantpressurescreeningtumortumorigenesis
项目摘要
Our long-term goal is to understand how the development of B-cell lymphomas is influenced by infection
and the antigen specificity of their surface-bound B-cell receptors (BCR). The objective in this proposal is to
understand how Pf and EBV cooperate to promote and maintain eBL. It is our central hypothesis that Pf infection
promotes EBV-mediated B-cell proliferation, Pf antigens are recognized by the EBV-infected BCR promoting the
BL-characteristic IgH/c-Myc translocation, and that eBL tumor maintenance is supported by EBV regulation of
tumor cell survival and Pf alteration of T-cell immunity. Our central hypothesis is premised on strong rationale
from the literature and our preliminary data characterizing the interplay between EBV and Pf in eBL. First, EBV
is clonally present in eBL cells suggesting both an early role in tumorigenesis and a requirement in tumor
maintenance. Second, malaria holoendemic areas are known hotspots for eBL where rates are as much as 100-
fold higher than in low/no malarial regions. Third, EBV infection of B cells potently activates expression of
activation-induced cytidine deaminase (AID), which is critical for BL-characteristic Ig/c-Myc translocations. While
the EBV latent protein EBNA2 opens B-cell chromatin upstream of the c-Myc gene promoting expression, it also
suppresses IgH transcription. Since IgH transcription is required for AID to gain access to the IgH locus and is
required for the IgH/c-Myc translocation, an additional factor must be affecting EBV-infected cells allowing this
translocation to occur. We hypothesize that Pf provides this factor in the form of antigen recognized by the EBV-
infected B-cell surface Ig. We propose that Pf infections provide both mitogenic signals to promote B-cell
proliferation as well as critical antigens driving AID-mediated BCR affinity maturation, which aberrantly leads to
the IgH/c-Myc translocation. Following the translocation, eBL tumors must withstand strong pressure from the
immune system against both the virus and tumor neoantigens. Our recent work indicates a strong suppressive
influence of Pf infection in vivo on CD8 T-cell recognition of EBV and eBL that we propose supports tumor
maintenance. The rationale for this proposal is that understanding the molecular mechanisms of eBL initiation
and pathogenesis vis-à-vis viral and parasite co-infection will provide us with a platform for understanding the
role of BCR specificity in B lymphomagenesis as well as how Pf infection influences immune surveillance to
support tumor maintenance. We plan to test our central hypothesis by pursuing the following three specific aims:
1) to determine the role of P. falciparum in collaborating with EBV to induce B-cell proliferation and tumorigenesis,
2) to determine the role of P. falciparum antigens as the critical trigger of the IgH/c-Myc translocation in eBL, and
3) to determine the interplay between EBV and P. falciparum immune alterations in eBL tumor maintenance.
我们的长期目标是了解b细胞淋巴瘤的发展如何受到感染的影响
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Micah A. Luftig其他文献
Comparison of nanopore with illumina whole genome assemblies of the Epstein-Barr virus in Burkitt lymphoma
- DOI:
10.1038/s41598-025-94737-0 - 发表时间:
2025-03-31 - 期刊:
- 影响因子:3.900
- 作者:
Isaac E. Kim;Abebe A. Fola;Enrique Puig;Titus Kipkemboi Maina;Sin Ting Hui;Hongyu Ma;Kaleb Zuckerman;Eddy O. Agwati;Alec Leonetti;Rebecca Crudale;Micah A. Luftig;Ann M. Moormann;Cliff Oduor;Jeffrey A. Bailey - 通讯作者:
Jeffrey A. Bailey
Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
- DOI:
10.1186/s13059-021-02405-z - 发表时间:
2021-06-17 - 期刊:
- 影响因子:9.400
- 作者:
Nisha Padmanabhan;Huang Kie Kyon;Arnoud Boot;Kevin Lim;Supriya Srivastava;Shuwen Chen;Zhiyuan Wu;Hyung-Ok Lee;Vineeth T. Mukundan;Charlene Chan;Yarn Kit Chan;Ong Xuewen;Jason J. Pitt;Zul Fazreen Adam Isa;Manjie Xing;Ming Hui Lee;Angie Lay Keng Tan;Shamaine Ho Wei Ting;Micah A. Luftig;Dennis Kappei;Warren D. Kruger;Jinsong Bian;Ying Swan Ho;Ming Teh;Steve George Rozen;Patrick Tan - 通讯作者:
Patrick Tan
Epstein-Barr virus induces germinal center light zone chromatin architecture and promotes survival through enhancer looping at the emBCL2A1/em locus
爱泼斯坦-巴尔病毒诱导生发中心亮区染色质结构,并通过 emBCL2A1/em 位点的增强子环化促进存活
- DOI:
10.1128/mbio.02444-23 - 发表时间:
2023-12-11 - 期刊:
- 影响因子:4.700
- 作者:
Joanne Dai;Elliott D. SoRelle;Emma Heckenberg;Lingyun Song;Jana M. Cable;Gregory E. Crawford;Micah A. Luftig;Alan N. Engelman - 通讯作者:
Alan N. Engelman
Micah A. Luftig的其他文献
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{{ truncateString('Micah A. Luftig', 18)}}的其他基金
Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas
定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性
- 批准号:
10706553 - 财政年份:2022
- 资助金额:
$ 64.04万 - 项目类别:
Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas
定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性
- 批准号:
10541348 - 财政年份:2022
- 资助金额:
$ 64.04万 - 项目类别:
Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis
剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用
- 批准号:
10204966 - 财政年份:2019
- 资助金额:
$ 64.04万 - 项目类别:
Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis
剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用
- 批准号:
10671667 - 财政年份:2019
- 资助金额:
$ 64.04万 - 项目类别:
Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence
定义 Epstein-Barr 病毒持续存在和复发的机制
- 批准号:
10437789 - 财政年份:2016
- 资助金额:
$ 64.04万 - 项目类别:
Targeting Apoptosis and Immune Control of Epstein-Barr Virus Infected Tonsillar B Cells
针对 Epstein-Barr 病毒感染的扁桃体 B 细胞的凋亡和免疫控制
- 批准号:
9237256 - 财政年份:2016
- 资助金额:
$ 64.04万 - 项目类别:
Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence
定义 Epstein-Barr 病毒持续存在和复发的机制
- 批准号:
10599350 - 财政年份:2016
- 资助金额:
$ 64.04万 - 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
- 批准号:
10663313 - 财政年份:2011
- 资助金额:
$ 64.04万 - 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
- 批准号:
8187400 - 财政年份:2011
- 资助金额:
$ 64.04万 - 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
- 批准号:
8843606 - 财政年份:2011
- 资助金额:
$ 64.04万 - 项目类别:
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