The pluripotency regulator Prdm14 initiates cancer by epigenetic mechanisms

多能性调节因子 Prdm14 通过表观遗传机制引发癌症

• 批准号: 8898738
• 负责人: MONICA J. JUSTICE
• 金额: $ 32.98万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-28 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898738
• 关键词: Acute T Cell Leukemia; Address; Adult; Aftercare; Aneuploidy; Animals; Behavior; Binding; Biochemical; Biological Assay; Breast; Cancer Relapse; Cell Separation; Cells; Chromatin; Chromosomal Rearrangement; Colon; Complex; Copy Number Polymorphism; Cultured Cells; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; Derivation procedure; Development; Disease; Double Strand Break Repair; Drug resistance; Epigenetic Process; Event; Flow Cytometry; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Recombination; Genomic Instability; Genomic Segment; Genomic approach; Goals; Health; Human; Life; Link; Lymphoblastic Leukemia; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Mining; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Mutation; NOTCH1 gene; Ovarian; Pharmaceutical Preparations; Play; Property; Proteins; RNA Sequences; Radiation; Recurrent disease; Relapse; Reporter; Role; SET Domain; Signal Transduction; Somatic Cell; Stem cells; Structure of primordial sex cell; Therapeutic Intervention; Tissues; Untranslated RNA; Work; X Chromosome; Xenograft Model; anticancer research; base; cancer cell; cancer initiation; cancer prevention; cancer type; cell type; chemotherapeutic agent; chromatin remodeling; clinically relevant; combinatorial; demethylation; design; genome integrity; histone methyltransferase; human data; interest; leukemia; lung melanoma; molecular marker; mouse model; pluripotency; preclinical study; prevent; programs; protein complex; research study; response; self-renewal; stem; therapy resistant; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Drug resistance and cancer relapse are attributed to the persistence of stem cells. The PR/SET domain protein PRDM14 regulates a cell's pluripotent potential to initiate and progress cancer through epigenetic events that are molecular signatures of stem cells. Normally, PRDM14 uses epigenetic mechanisms to establish the pluripotency of primordial germ cells, and its role in cancer is similar. PRDM14's widespread expression in many tumor types, including breast, ovarian, colon, lung, melanoma and lymphoblastic leukemia implies that it is commonly involved in epigenetic events to initiate cancer. This proposal challenges paradigms by suggesting that PRDM14 regulates a somatic cell's pluripotent potential to generate C-ICs as it promotes genomic instability, allowing it to cause tumors in many cell types. PRDM14 is a prime target for therapeutic intervention, because of its restricted expression to only a few cells in the body. Key to this project is that unique inducible mouse models will be exploited to examine events during tumor development, progression and relapse. Experiments that address three basic questions will be performed: what biochemical mechanisms does Prdm14 use to establish self-renewal to initiate cancer, how do the initiating cells maintain self-renewal in the tumor, and how does PRDM14 perturb genome integrity within these cells to progress malignancy? The first aim will use cutting edge genomic approaches to confirm Prdm14's binding targets and identify its protein partners, while it determines how Prdm14 alters chromatin to reset pluripotency in pre- leukemia cells. The second aim will determine the properties of Prdm14 pre-leukemia cells using flow cytometry, cellular and molecular profiling approaches. The third aim will determine how PRDM14 catalyzes chromosomal rearrangements, leading to copy number variation in the tumors that cause specific driver mutations such as activated NOTCH1 through recombination. These studies propose a genetic strategy to inhibit recombination and a drug treatment strategy designed against targets downstream of PRDM14's action to prevent the growth of tumors in the mouse model. The mouse models allow the behavior of cancer cells to be monitored from the beginning, mark cells for isolation, and follow their lineage potential. Data from human tumors will be mined and compared with mouse tumors throughout the study and mouse leukemia will be compared with human leukemia in Aim 3 to demonstrate clinical relevance. Although mouse leukemia models are exploited, the work will have far-reaching applications to all cancers. PRDM14's limited normal expression in adults indicates that PRDM14 or its initial regulatory targets are key candidates for a therapy directed against cells that express it abnormally. Therefore, PRDM14 could prove to be a universal target in C-ICs.

描述（由申请人提供）：耐药性和癌症复发归因于干细胞的持久性。PR/SET结构域蛋白PRDM 14通过作为干细胞分子特征的表观遗传事件调节细胞的多能潜能以引发和发展癌症。通常，PRDM 14使用表观遗传机制来建立原始生殖细胞的多能性，其在癌症中的作用类似。PRDM 14在包括乳腺癌、卵巢癌、结肠癌、肺癌、黑色素瘤和淋巴母细胞白血病在内的许多肿瘤类型中的广泛表达意味着它通常参与表观遗传事件以引发癌症。该提案通过表明PRDM 14调节体细胞的多能潜能以产生C-IC来挑战范式，因为它促进基因组不稳定性，使其能够在许多细胞类型中引起肿瘤。PRDM 14是治疗干预的主要靶标，因为其仅在体内少数细胞中限制表达。该项目的关键是将利用独特的诱导型小鼠模型来检查肿瘤发生、进展和复发期间的事件。将进行解决三个基本问题的实验：Prdm 14使用什么生化机制来建立自我更新以引发癌症，启动细胞如何在肿瘤中保持自我更新，以及PRDM 14如何扰乱这些细胞内的基因组完整性以发展恶性肿瘤？第一个目标将使用尖端的基因组方法来确认Prdm 14的结合靶点并识别其蛋白质伴侣，同时确定Prdm 14如何改变染色质以重置白血病前细胞的多能性。第二个目标将使用流式细胞术、细胞和分子分析方法确定Prdm 14前白血病细胞的特性。第三个目标将确定PRDM 14如何催化染色体重排，导致肿瘤中的拷贝数变异，从而导致特定的驱动突变，例如通过重组激活NOTCH 1。这些研究提出了一种抑制重组的遗传策略和一种针对PRDM 14作用下游靶点设计的药物治疗策略，以防止小鼠模型中肿瘤的生长。小鼠模型允许从一开始就监测癌细胞的行为，标记细胞进行分离，并跟踪其谱系潜力。在整个研究期间，将采集人肿瘤数据并与小鼠肿瘤进行比较，在目标3中，将小鼠白血病与人白血病进行比较，以证明临床相关性。虽然小鼠白血病模型被利用，但这项工作将对所有癌症产生深远的应用。PRDM 14在成人中有限的正常表达表明，PRDM 14或其初始调节靶标是针对异常表达它的细胞的治疗的关键候选物。因此，PRDM 14可以被证明是C-IC中的通用目标。