Analysis and Therapeutic Targeting of the Linear-Ubiquitination Pathway in Hodgkin Lymphoma
霍奇金淋巴瘤线性泛素化途径的分析和治疗靶向
基本信息
- 批准号:10622597
- 负责人:
- 金额:$ 41.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigensApoptosisB cell differentiationB-LymphocytesBiological AssayBiologyC-terminalCRISPR libraryCRISPR screenCell SurvivalCell surfaceCellsClinicalCoculture TechniquesComplexDevelopmentDiagnosisDiseaseEngraftmentEnzymesGene Expression ProfilingGenesGrowthHodgkin DiseaseHumanHuman Herpesvirus 4ImmuneImmune checkpoint inhibitorImmune responseImmune systemImmunotherapyIn VitroIn complete remissionInflammatoryInterleukin-13InterventionKnowledgeLibrariesLymphomaMalignant - descriptorMalignant lymphoid neoplasmMediatingMinority GroupsMolecularMusMutationOutcomeOverlapping GenesPathogenesisPathologicPathway interactionsPatientsPeripheral Blood Mononuclear CellPhenotypeProcessProductionProliferatingProteinsProteomicsPublic HealthRecurrenceReed-Sternberg-like CellRefractoryRefractory DiseaseRelapseRoleSTAT6 geneSamplingSignal TransductionSurvival RateSystemT-Cell ProliferationTNFRSF8 geneTestingTherapeuticTranslatingTumor EscapeUbiquitinUbiquitinationXenograft ModelZinc Fingerscell growthcytokineefficacy evaluationhumanized mouseimmune checkpointimmune clearanceimprovedin vivoin vivo evaluationinhibitorinsightloss of functionmolecular pathologymutantmutational statusneoplastic cellnovelnovel strategiesnovel therapeutic interventionpreventprogrammed cell death ligand 1programsrare cancerresponsescreeningsmall molecular inhibitortargeted treatmenttherapeutic developmenttherapeutic targettherapeutically effectivetranscriptome sequencingtumortumor growthtumor initiationtumor-immune system interactionsyoung adult
项目摘要
PROJECT SUMMARY
Hodgkin lymphoma (HL) is the most common (6,000 to 7,000 new cases per year) lymphoma subtype in young
adulthood. Although there has been great progress during the last few decades, the survival rate for patients
diagnosed at an advanced stage or with relapsed/refractory disease remains low. The current understanding of
the biology of the disease has been translated into the development and approval of therapeutic agents that
target HL-specific antigens or immune checkpoint pathways. However, the number of patients in complete
remission has been low, and relapse frequently develops, leading to poor outcomes. Thus, a clearer
understanding of the molecular pathology of HL is necessary to develop new treatment strategies. HL is
characterized by a minority population of malignant Hodgkin and Reed/Sternberg (HRS) cells in a background
of dense inflammatory cells. HRS cells have lost their B cell phenotype, however, and escaped from BCR-
mediated apoptosis and immune elimination. Therefore, two major questions remain: (a), how do HRS cells
escape the control of the immune system; (b), how do they survive despite the absence of BCR expression? To
address these gaps in knowledge, we applied an unbiased high throughput CRISPR screening, and identified
an essential role for the linear ubiquitin chain assembly complex (LUBAC) in HL pathogenesis. Our preliminary
studies demonstrated that LUBAC activity promotes HRS cell survival and immune escape, which significantly
overlaps with mutation status of the most recurrent genetically altered gene in HL, A20. Clinically, LUBAC activity
is consistently elevated in most primary HL cases, and this is correlated with low A20 expression. Moreover,
using RNA-seq analysis, we identified a set of LUBAC-regulated genes in HL that overlapped significantly with
signatures reflecting NF-κB and JAK-STAT activities, as well as TH2 cytokines and cell surface
immunosuppressive molecules. Unexpectedly, our BioID proteomic screening reveals a CD30-LUBAC complex
in HL, suggesting the role of LUBAC-A20 axis in the CD30 mediated NF-κB signaling, TH2 cytokine production,
and STAT6 activation. Finally, a highly specific LUBAC small molecular inhibitor shows promising activity against
HL in vitro and in a mouse xenograft model. Altogether, these findings provide strong support for our hypothesis
that the LUBAC-A20 axis regulates HL pathogenesis, and that targeting LUBAC could be a novel therapeutic
strategy in this disease. In this study, we will: 1) investigate the mechanistic basis by which the LUBAC-A20
axis supports HRS survival and proliferation; 2) evaluate how linear-ubiquitin-dependent signaling regulates the
molecular circuitry that drives tumor immune escape of HL; and 3) exploit the therapeutic potential of targeting
LUBAC to provide novel intervention strategies for both targeted and immune therapies in HL. These studies
promise to reveal critical insights into the molecular circuitry that drives this lymphoid cancer, as well as provide
unique opportunities for the development of novel strategies for both targeted and immune therapies to treat HL.
项目摘要
霍奇金淋巴瘤(HL)是年轻的最常见(每年6,000至7,000例新病例)淋巴瘤亚型
成年。尽管在过去的几十年中取得了长足的进步,但患者的存活率
在晚期或中继/难治性疾病的诊断仍然很低。当前对
该疾病的生物学已转化为治疗剂的发展和批准
靶HL特异性抗原或免疫检查点途径。但是,完整的患者人数
缓解量很低,缓解经常会导致结果不佳。那,更清晰
了解HL的分子病理对于制定新的治疗策略是必要的。 HL是
以少数恶性霍奇金和芦苇/sternberg(HRS)细胞为特征
致密的炎症细胞。但是
介导的凋亡和免疫进化。因此,仍然存在两个主要问题:(a),HRS细胞如何
逃脱免疫系统的控制; (b),尽管没有BCR表达,但它们如何生存?到
在知识中解决这些差距,我们应用了公正的高通量CRISPR筛选,并确定了
线性泛素链组件复合物(LUBAC)在HL发病机理中的重要作用。我们的初步
研究表明,LUBAC活性促进了HRS细胞存活和免疫逃生,这显着
与HL中最反复发生的基因的突变状态的重叠,A20。在临床上,卢巴克活动
在大多数主要的HL病例中始终升高,这与低A20表达相关。而且,
使用RNA-seq分析,我们确定了HL中的一组LUBAC调节的基因,该基因与
反映NF-κB和JAK-STAT活动的特征,以及Th2细胞因子和细胞表面
免疫抑制分子。出乎意料的是,我们的生物分子蛋白质组学筛选揭示了CD30-Lubac复合物
在HL中,表明LUBAC-A20轴在CD30介导的NF-κB信号传导中的作用,Th2细胞因子的产生,
和STAT6激活。最后,高度特异的lubac小分子抑制剂显示出有望的活性
HL体外和鼠标定征模型。总之,这些发现为我们的假设提供了强有力的支持
LUBAC-A20轴调节HL发病机理,而靶向LUBAC可能是一种新的治疗方法
这种疾病的策略。在这项研究中,我们将:1)研究lubac-A20的机械基础
轴支持HRS的存活和增殖; 2)评估线性 - 泛素依赖性信号传导如何调节
驱动HL肿瘤免疫逃生的分子电路; 3)利用靶向的治疗潜力
LUBAC为HL中的靶向和免疫疗法提供新颖的干预策略。这些研究
有望揭示对驱动这种淋巴类癌的分子电路的关键见解,并提供
为靶向和免疫治疗HL制定新型策略的独特机会。
项目成果
期刊论文数量(1)
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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Yibin Yang其他文献
Yibin Yang的其他文献
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{{ truncateString('Yibin Yang', 18)}}的其他基金
Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy
研究间变性大细胞淋巴瘤中的 IL-1R 通路以进行靶向治疗
- 批准号:
10385771 - 财政年份:2021
- 资助金额:
$ 41.92万 - 项目类别:
Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy
研究间变性大细胞淋巴瘤中的 IL-1R 通路以进行靶向治疗
- 批准号:
10599170 - 财政年份:2021
- 资助金额:
$ 41.92万 - 项目类别:
Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy
研究间变性大细胞淋巴瘤中的 IL-1R 通路以进行靶向治疗
- 批准号:
10184596 - 财政年份:2021
- 资助金额:
$ 41.92万 - 项目类别:
Analysis and Therapeutic Targeting of the Linear-Ubiquitination Pathway in Hodgkin Lymphoma
霍奇金淋巴瘤线性泛素化途径的分析和治疗靶向
- 批准号:
10374912 - 财政年份:2021
- 资助金额:
$ 41.92万 - 项目类别:
Analysis and Therapeutic Targeting of the Linear-Ubiquitination Pathway in Hodgkin Lymphoma
霍奇金淋巴瘤线性泛素化途径的分析和治疗靶向
- 批准号:
10210535 - 财政年份:2021
- 资助金额:
$ 41.92万 - 项目类别:
Analysis and Therapeutic Targeting Non-proteolytic Protein Ubiquitination in Diffuse Large B Cell Lymphoma
弥漫性大 B 细胞淋巴瘤中非蛋白水解蛋白泛素化的分析和治疗
- 批准号:
9339622 - 财政年份:2016
- 资助金额:
$ 41.92万 - 项目类别:
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