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：
10374912
负责人：
Yibin Yang
金额：
$ 42.78万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
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：
https://reporter.nih.gov/project-details/10374912
关键词：
Address Antigens Apoptosis B cell differentiation B-Lymphocytes Biological Assay Biology C-terminal CRISPR library CRISPR screen Cell Survival Cell surface Cells Clinical Coculture Techniques Complex Development Diagnosis Disease Enzymes Gene Expression Profiling Genes Growth Hodgkin Disease Human Human Herpesvirus 4 Immune Immune checkpoint inhibitor Immune response Immune system Immunotherapy In Vitro In complete remission Inflammatory Interleukin-13 Intervention Knowledge Lead Libraries Lymphoma Malignant - descriptor Malignant lymphoid neoplasm Mediating Minority Groups Molecular Mus Mutation Outcome Pathogenesis Pathologic Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Process Production Proteins Proteomics Public Health Recurrence Reed-Sternberg Cells Refractory Refractory Disease Relapse Role STAT6 gene Sampling Signal Transduction Survival Rate System T-Cell Proliferation TNFRSF8 gene Testing Therapeutic Translating Tumor Escape Ubiquitin Ubiquitination Xenograft Model Zinc Fingers base cell growth cytokine efficacy evaluation humanized mouse immune checkpoint immune clearance improved in vivo in vivo evaluation inhibitor insight loss of function molecular pathology mutant mutational status neoplastic cell novel novel strategies novel therapeutic intervention prevent programmed cell death ligand 1 programs rare cancer response screening small molecular inhibitor targeted treatment therapeutic development therapeutic target therapeutically effective transcriptome sequencing treatment strategy tumor tumor growth tumor-immune system interactions young 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）是年轻人中最常见的（6,000至7,000个新的Casses Perth）淋巴瘤亚型成年。在高级阶段或复发/难治性疾病中诊断出对目前的理解。该疾病的生物学已转化为治疗剂的发展和熟悉的生物学目标HL特异性抗原或免疫检查点途径。缓解率很低，复发经常发展，导致结果较差了解HL的分子病理对于制定新的治疗策略是必要的。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。介导的凋亡和免疫消除。逃脱了免疫系统的控制；解决知识的差距，我们应用了公正的高量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研究表明，LUBAC活性促进了HRS细胞的存活和免疫逃逸，这显着在HL中，最复发的基因基因的突变状态A20在临床上，lubac活性在大多数主要的HL病例中始终如一，这与低A20表达相关。使用RNA-seq分析，我们确定了HL中的一组lubac调控基因，这些基因与。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性分子。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，最终，STAT6激活。 HL体外和小鼠定位图 Lubac-A20轴调节HL发病机理，而靶向Lubac可能是一种新型的治疗方法在这项研究中，我们将：1）研究Lubac-A20的机械基础轴支持HRS的存活率和繁殖力； 2）评估线性 - 泛素依赖性的信号驱动HL的肿瘤免疫的分子电路； 3） LUBAC为HL的靶向和免疫疗法提供新的干预策略承诺将批判性见解介绍驱动这种淋巴类癌的分子电路，并提供为靶向和免疫治疗HL制定新型策略的独特机会。