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续性。 PR/SET结构域PRDM14通过表观遗传事件是干细胞的分子特征来调节细胞的多能潜力，以启动和进展癌症。通常，PRDM14使用表观遗传机制来建立原始生殖细胞的多能性，并且其在癌症中的作用相似。 PRDM14在许多肿瘤类型中的广泛表达，包括乳腺癌，卵巢，结肠，肺癌，黑色素瘤和淋巴细胞性白血病，这意味着它通常参与表观遗传事件以引发癌症。该提议通过建议PRDM14调节体细胞的多能潜力来产生C-IS，从而促进基因组不稳定性，从而使其在许多细胞类型中引起肿瘤，从而挑战了范式。 PRDM14是治疗干预的主要靶标，因为它的表达仅限于体内几个细胞。该项目的关键是，将利用独特的诱导小鼠模型来检查肿瘤发育，进展和复发期间的事件。将解决三个基本问题的实验：PRDM14用于建立自我更新以启动癌症的生化机制，这些启动细胞如何在肿瘤中维持自我更新，PRDM14在这些细胞中如何扰动基因组完整性在这些细胞中如何进步恶意？第一个目的将使用尖端基因组方法来确认PRDM14的结合靶标并确定其蛋白质伴侣，而它决定PRDM14如何改变染色质以重置 - 白血病细胞中的多能性。第二个目标将使用流式细胞术，细胞和分子分析方法来确定PRDM14前白血病细胞的特性。第三个目标将决定PRDM14如何催化染色体重排，从而导致肿瘤的拷贝数变化，从而导致特定的驱动突变（例如通过重组激活的Notch1）。这些研究提出了一种遗传策略，以抑制重组和针对PRDM14在小鼠模型中肿瘤生长的行动下游靶标而设计的药物治疗策略。小鼠模型允许从一开始监测癌细胞的行为，标记细胞进行隔离，并遵循其谱系潜力。将挖掘来自人类肿瘤的数据，并将其与整个研究过程中的小鼠肿瘤进行比较，而小鼠白血病将与AIM 3中的人白血病进行比较，以证明临床相关性。尽管利用了鼠标白血病模型，但该作品将对所有癌症都有深远的应用程序。 PRDM14在成年人中的正常表达有限，表明PRDM14或其初始调节靶标是针对针对细胞异常表达其细胞的疗法的关键候选。因此，PRDM14可能被证明是C-IS中的普遍目标。