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: 9267938
• 负责人: MONICA J. JUSTICE
• 金额: $ 32.47万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267938
• 关键词: Acute T Cell Leukemia; Address; Adult; Aftercare; Alpha Cell; Aneuploidy; Animals; Behavior; Binding; Biochemical; Biological Assay; Breast; Cancer Model; Cancer Relapse; Cell Differentiation process; 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 Targeting; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genomic Instability; Genomic Segment; Genomic approach; Goals; Human; Link; Lung; Lymphoblastic Leukemia; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Monitor; Mus; NOTCH1 gene; Ovarian; Pharmacotherapy; Play; Preleukemia; Property; Proteins; Radiation; Recurrent disease; Relapse; Reporter; Research; Role; SET Domain; Signal Transduction; Somatic Cell; Stem cells; Structure of primordial sex cell; Tertiary Protein Structure; Therapeutic Intervention; Tissues; Untranslated RNA; Work; X Chromosome; Xenograft Model; actionable mutation; cancer cell; cancer initiation; cancer prevention; cancer type; cell type; chemotherapeutic agent; clinically relevant; combinatorial; demethylation; design; experimental study; genome integrity; histone methyltransferase; human data; interest; leukemia; melanoma; molecular marker; mouse model; pluripotency; preclinical study; prevent; programs; protein complex; public health relevance; response; self-renewal; stem; targeted treatment; therapy resistant; transcription factor; transcriptome; 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(申请人提供)：耐药和癌症复发归因于干细胞的持久性。PR/SET结构域蛋白PRDM14通过作为干细胞分子特征的表观遗传事件调节细胞启动和进展癌症的多潜能。正常情况下，PRDM14使用表观遗传机制来建立原始生殖细胞的多能性，它在癌症中的作用类似。PRDM14‘S广泛表达于乳腺癌、卵巢癌、结肠癌、肺癌、黑色素瘤和淋巴母细胞白血病等多种肿瘤组织中，提示其常参与表观遗传学事件，从而引发癌症。这一提议挑战了范式，认为PRDM14调节体细胞产生C-IC的多潜能，因为它促进了基因组的不稳定性，使其能够导致许多细胞类型的肿瘤。PRDM14是治疗干预的主要靶点，因为它仅限于体内的几个细胞表达。该项目的关键是将利用独特的可诱导小鼠模型来检查肿瘤发生、进展和复发过程中的事件。将进行三个基本问题的实验：PRDM14使用什么生化机制来建立启动癌症的自我更新，启动细胞如何在肿瘤中保持自我更新，以及PRDM14如何扰乱这些细胞内的基因组完整性以进展为恶性肿瘤？第一个目标将使用尖端基因组学方法来确认PRDM14的S结合靶点并确定其蛋白质伙伴，同时它将确定PRDM14如何改变染色质以重置白血病前期细胞的多能性。第二个目标将使用流式细胞术、细胞和分子图谱方法来确定PRDM14白血病前期细胞的特性。第三个目标将确定PRDM14如何催化染色体重排，导致肿瘤中拷贝数的变化，从而导致特定的驱动程序突变，例如通过重组激活的NOTCH1。这些研究提出了抑制重组的遗传策略和针对PRDM14下游靶点的药物治疗策略，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，标记细胞以进行分离，并跟踪它们的谱系潜力。在整个研究过程中，将挖掘人类肿瘤的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类白血病进行比较，以证明临床相关性。尽管利用了小鼠白血病模型，但这项工作将对所有癌症产生深远的应用。PRDM14的S在成人中的有限正常表达表明，PRDM14或其最初的调控靶点是针对其异常表达的细胞的治疗的关键候选。因此，PRDM14可能被证明是C-IC的通用目标。

项目成果

Off to a Bad Start: Cancer Initiation by Pluripotency Regulator PRDM14.

糟糕的开始：多能性调节剂 PRDM14 引发癌症。

• DOI: 10.1016/j.tig.2019.04.004
• 发表时间: 2019
• 期刊: Trends in genetics : TIG
• 作者: Tracey,LaurenJ;Justice,MonicaJ
• 通讯作者: Justice,MonicaJ

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.

多能性调节因子 PRDM14 需要造血调节因子 CBFA2T3 来引发小鼠白血病。

• DOI: 10.1158/1541-7786.mcr-18-1327
• 发表时间: 2019
• 期刊: Molecular cancer research : MCR
• 作者: Tracey,LaurenJ;Brooke-Bisschop,Travis;Jansen,PascalWTC;Campos,EricI;Vermeulen,Michiel;Justice,MonicaJ
• 通讯作者: Justice,MonicaJ

Tissue-Specific Regulation of Oncogene Expression Using Cre-Inducible ROSA26 Knock-In Transgenic Mice.

• DOI: 10.1002/9780470942390.mo140150
• 发表时间: 2015-06-01
• 期刊: Current protocols in mouse biology
• 作者: Carofino BL;Justice MJ
• 通讯作者: Justice MJ