Transcriptional Control of Cellular Survival and Proliferation in KSHV-transformed B Cells

KSHV 转化的 B 细胞中细胞存活和增殖的转录控制

基本信息

批准号：
10380596
负责人：
Eva Henriette Gottwein
金额：
$ 36.44万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-13 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380596
关键词：
AIDS related cancer AIDS/HIV problem Acquired Immunodeficiency Syndrome Address B Cell Proliferation B-Cell Lymphomas B-Lymphocytes BCL2L11 gene CCND2 gene Cancer Etiology Cancerous Cell Line Cell Proliferation Cell Survival Cellular biology ChIP-seq Complex DNA Data Dependence Distal Drug Addiction Drug Targeting Elements Enhancers Environment Epigenetic Process Event Exhibits Gene Expression Genes Genetic Transcription Genomic approach Hematopoietic Neoplasms Homologous Gene Human Human Herpesvirus 8 IRF4 gene Immunomodulators In Vitro Individual Interferons Lymphoid Lymphoma cell MYC gene Malignant Neoplasms Mediating Mediator of activation protein Molecular Oncogenic Outcome Public Health Regulatory Element Repression Response Elements Role Test Result Testing Therapeutic Therapeutic Intervention Transcriptional Regulation Transcriptional Silencer Elements Tumor Suppressor Proteins Viral Work base cofactor effusion experimental study functional genomics improved in vivo inhibitor innovation mRNA sequencing neoplastic cell novel novel therapeutic intervention overexpression primary effusion lymphoma programs promoter synergism therapeutic candidate transcription factor transcriptional reprogramming viral interferon regulatory factor viral interferon regulatory factor-3

项目摘要

SUMMARY Kaposi’s sarcoma-associated herpesvirus (KSHV) is a major cause of cancer in the context of HIV/AIDS. We recently showed that KSHV-transformed primary effusion lymphoma (PEL) cell lines exhibit a strong requirement for the cellular lymphoid transcription factor IRF4. This finding places PEL into an emerging group of blood cancers where IRF4 is a key oncogenic driver. A detailed understanding of the oncogenic roles of IRF4 has not been achieved in any of these cancers, but evidence suggests that IRF4 functions as a master transcription factor that induces extensive epigenetic and transcriptional reprogramming. In PEL, IRF4 is required for overexpression of the MYC oncogene, but how KSHV controls IRF4, the molecular mechanism by which IRF4 regulates MYC, and whether IRF4 acts solely through MYC or has additional oncogenic roles is unknown. The long-term objective of this proposal is to determine the downstream effects that underlie the oncogenic roles of IRF4 in PEL and to use our results to develop novel therapeutic strategies. The central hypothesis of this proposal is that KSHV-induced, IRF4-dependent oncogenic transcriptional reprogramming is required for tumor cell survival and proliferation in PEL. This hypothesis is premised on our extensive preliminary work, which has identified both KSHV-encoded and cellular transcription factors that control IRF4 expression and function in PEL. Based on ChIP-Seq and mRNA-Seq experiments, we specifically hypothesize that IRF4, together with its viral and cellular co-factors, associates with promoters and distal cis-regulatory elements to drive an IRF4-dependent oncogenic transcription program, which involves both the silencing of “toxic” tumor suppressors and the overexpression of several essential survival genes, including MYC, but also others. To test our hypothesis, we propose two Specific Aims, i.e. we will: (1) determine which toxic genes must be silenced by IRF4 to promote PEL cell viability and proliferation, and (2) determine which IRF4-stimulated genes are essential IRF4 effectors in PEL cells. Several of the already identified candidates for IRF4 effectors are high-confidence drug targets. We will therefore exploit our results in both aims to identify and test novel therapeutic strategies, in vitro and in vivo. This work uses a cutting-edge approach that integrates hypothesis-driven experiments with unbiased functional genomics approaches. The proposed study is innovative, because the oncogenic outcome of transcriptional reprogramming in the context of KSHV-associated malignancies has not been studied. The proposed work is significant, because it will uncover oncogenic roles of IRF4 in KSHV-mediated B cell proliferation and survival. In addition, results will inform our understanding of IRF4 in B cell biology and its oncogenic role in several hematopoietic malignancies. Results will be impactful, because our studies of IRF4 dependency are expected to result in improved strategies for therapeutic intervention in this incurable cancer.

概括卡波西肉瘤相关疱疹病毒 (KSHV) 是艾滋病毒/艾滋病背景下癌症的主要原因。最近表明，KSHV 转化的原发性渗出性淋巴瘤 (PEL) 细胞系表现出强烈的需求细胞淋巴转录因子 IRF4 这一发现将 PEL 纳入了一个新兴的血液组中。 IRF4 是关键致癌驱动因素的癌症尚未详细了解 IRF4 的致癌作用。这些癌症中的任何一种都已实现，但有证据表明 IRF4 充当主转录在 PEL 中，IRF4 是诱导广泛表观遗传和转录重编程的因子。 MYC癌基因的过度表达，但KSHV如何控制IRF4，IRF4的分子机制调节 MYC，IRF4 是否仅通过 MYC 发挥作用还是具有其他致癌作用尚不清楚。该提案的长期目标是确定致癌作用的下游影响 PEL 中的 IRF4 并利用我们的结果来开发新的治疗策略这是这一点的中心假设。提议认为，KSHV 诱导的 IRF4 依赖性致癌转录重编程是肿瘤发生所必需的 PEL 中的细胞存活和增殖这一假设是以我们广泛的前期工作为前提的。鉴定出控制 PEL 中 IRF4 表达和功能的 KSHV 编码因子和细胞转录因子。基于 ChIP-Seq 和 mRNA-Seq 实验，我们特别针对 IRF4 及其病毒和细胞辅助因子，与启动子和远端顺式调节元件相关联，驱动 IRF4 依赖性致癌转录程序，涉及“有毒”肿瘤抑制因子的沉默和一些重要的生存基因的过度表达，包括 MYC，还有其他基因。为了检验我们的假设，我们。提出两个具体目标，即我们将：（1）确定哪些有毒基因必须被 IRF4 沉默以促进 PEL 细胞活力和增殖，以及 (2) 确定哪些 IRF4 刺激基因是必需的 IRF4 效应子一些已经确定的 IRF4 效应子候选物是高可信度的药物靶点。因此，我们将利用我们的结果来确定和测试体外和体内的新治疗策略。这项工作采用了一种前沿方法，将假设驱动的实验与无偏函数相结合所提出的研究具有创新性，因为转录的致癌结果。尚未对 KSHV 相关恶性肿瘤中的重编程进行研究。意义重大，因为它将揭示 IRF4 在 KSHV 介导的 B 细胞增殖和存活中的致癌作用。此外，结果将有助于我们了解 B 细胞生物学中的 IRF4 及其在多种癌症中的致癌作用。结果将是有影响力的，因为我们对 IRF4 依赖性的研究是预期的。从而改进针对这种无法治愈的癌症的治疗干预策略。