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

• 批准号: 10524178
• 负责人: Eva Henriette Gottwein
• 金额: $ 1.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/10524178
• 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

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 在艾滋病毒/艾滋病的背景下，卡波西肉瘤相关的疱疹病毒（KSHV）是癌症的主要原因。我们 最近表明，KSHV转化的原发性淋巴瘤（PEL）细胞系表现出很强的要求 用于细胞淋巴转录因子IRF4。这一发现将PEL放入新兴的血液中 IRF4是关键的致癌驱动器的癌症。对IRF4的致癌作用的详细理解尚未 在这些癌症中的任何一种中都是实现的，但证据表明IRF4起着主转录的作用 影响广泛表观遗传和转录重编程的因素。在PEL中，IRF4是必需的 Myc癌基因的过表达，但是KSHV如何控制IRF4，这是IRF4的分子机制 调节MYC，以及IRF4是否仅通过MYC起作用还是具有其他致癌作用是未知的。 该提案的长期目标是确定下游效应是构成致癌作用的基础的下游效应 pel中的IRF4并利用我们的结果来制定新的治疗策略。中心假设 建议是肿瘤需要KSHV诱导的，IRF4依赖性的致癌转录重编程 细胞存活和PEL中的增殖。这个假设以我们广泛的初步工作为前提， 鉴定出控制PEL中IRF4表达和功能的KSHV编码和细胞转录因子。 基于Chip-Seq和mRNA-Seq实验，我们特别假设IRF4及其病毒 和蜂窝联合因子，与启动子和远端顺式调节元素相关，以驱动IRF4依赖性 致癌转录程序，涉及“有毒”肿瘤补充剂的沉默和 包括MYC在内的几个基本生存基因的过表达，以及其他基因。为了检验我们的假设，我们 提案两个具体目标，即我们将：（1）确定必须将哪些有毒基因降低为IRF4才能促进 PEL细胞的活力和增殖，（2）确定哪些IRF4刺激的基因是必不可少的IRF4效应子 在pel细胞中。 IRF4生效者的几个已经确定的候选者是高信任药物靶标。我们 因此，将在体外和体内识别和测试新型治疗策略的两种旨在利用我们的结果。 这项工作采用了一种尖端的方法，该方法将假设驱动的实验与无偏功能相结合 基因组学方法。拟议的研究是创新的，因为转录的致癌结果 在KSHV相关的恶性肿瘤的背景下重新编程尚未研究。拟议的工作是 重要的是，因为它会发现IRF4在KSHV介导的B细胞增殖和存活中的致癌作用。 此外，结果将为我们在B细胞生物学中对IRF4的理解及其在几种中的致癌作用 造血恶性肿瘤。结果将有影响，因为我们对IRF4依赖性的研究有望 为了改善对这种无法治愈的癌症治疗干预的策略。