Oncogene Cooperativity in Leukemia Stem Cells

白血病干细胞中的癌基因协同作用

• 批准号: 9065508
• 负责人: Craig T. Jordan
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065508
• 关键词: Acute Myelocytic Leukemia; Address; Biological; Biological Models; Biology; Blast Phase; Cells; Computer Simulation; Computing Methodologies; Development; Disease; Drug Targeting; ERBB2 gene; Epithelial; Gene Expression; Gene Expression Profiling; Genes; Goals; Growth; Human; Individual; Leukemic Cell; Libraries; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Methodology; Methods; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Mus; Mutation; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Pilot Projects; Process; Property; Regimen; Reporting; Resistance; Role; SERPINB2 gene; Signal Transduction; Specimen; System; TP53 gene; Testing; Therapeutic; Treatment Protocols; base; bcr-abl Fusion Proteins; cell growth; drug discovery; genetic analysis; human disease; human tissue; improved; in vivo; inhibitor/antagonist; insight; leukemia; leukemic stem cell; leukemogenesis; malignant state; mouse model; new therapeutic target; novel; novel strategies; novel therapeutics; research study; response; restoration; small hairpin RNA; stem; stem cell biology; stem cell population; tool; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to define the molecular parameters that mediate oncogenic transformation of acute myeloid leukemia stem cells (LSCs). This objective is based on the overwhelming evidence that now exists regarding the role and biological properties of LSCs. Numerous studies have documented the existence of LSCs in both primary human tissues and mouse model systems. This biologically distinct subpopulation is responsible for the genesis and perpetuation of leukemic disease. Further, LSCs display significance resistance to conventional forms of therapy, making the development of novel regimens a high priority. For this application we have employed a novel strategy for the analysis of oncogene cooperativity as a means to elucidate the genes/pathways most central to malignancy. The approach employs global gene expression profiling as a tool to identify genes that are synergistically dysregulated as a consequence of co- expressing two cooperating oncogenes. Previous studies in a model of epithelial cancer have demonstrated that this strategy is highly effective, and indeed successfully yielded a number of novel mechanisms involved in tumor formation. We have applied this approach, known as identification of "cooperativity response genes" or CRGs in the context of a genetically defined murine model of blast crisis CML. The system, which employs dual expression of the BCR/ABL and Nup98/HoxA9 translocation products, has previously been characterized in several reports, and has a phenotypically defined LSC population. Our experiments have identified 72 genes that fulfill the CRG criteria in this model. Preliminary studies of one CRG, serpinB2, have indicated an important role for the gene in growth of leukemic cells in vivo. Further, analysis of the CRG expression profile has been performed using computational methods, which indicate that ERBB2 signaling may be important for leukemia cell growth/survival. Initial studies with a drug that targets ERBB2 have indicated a functional role for this pathway. Taken together, our preliminary indicate that CRG-based analysis of leukemia may be a powerful means by which to identify the mechanisms central to leukemogenesis. Based on the findings to date, we hypothesize that CRGs are highly enriched for critical regulators of leukemogenesis in our mouse model system. Further, we propose to investigate whether such genes are also important for the growth of primary human blast crisis CML. For both mouse and human studies, our emphasis will be on the analysis of CRGs in leukemic stem cell populations. Taken together, these studies will provide a comprehensive understanding of pathways and processes that mediate leukemic disease.

描述（由申请人提供）：该提案的长期目标是定义介导急性髓细胞性白血病干细胞（LSC）致癌性转化的分子参数。该目标是基于目前关于LSC的作用和生物学特性的压倒性证据。大量研究记录了原代人体组织和小鼠模型系统中LSC的存在。这种生物学上不同的亚群是为了使白血病疾病的起源和延续。此外，LSCs对常规治疗形式表现出显着性抗性，使新方案的发展成为很高的优先级。 对于此应用，我们采用了一种新型策略来分析致癌基因合作，以阐明最重要的恶性基因/途径。该方法采用全球基因表达分析作为一种工具来识别由于表达两种合作的癌基因而导致协同失调的基因。先前在上皮癌模型中的研究表明，该策略是非常有效的，并且实际上成功地产生了许多参与肿瘤形成的新机制。我们已经应用了这种方法，称为“合作反应基因”或CRG的识别，在遗传定义的爆炸危机CML模型的背景下。该系统采用BCR/ABL和NUP98/HOXA9易位产品的双重表达，此前已在几份报告中表征，并且具有表型定义的LSC群体。我们的实验已经确定了72个基因，这些基因满足了该模型中CRG标准。对一项CRG SerpinB2的初步研究表明，该基因在体内白血病细胞生长中起重要作用。此外，已经使用计算方法对CRG表达曲线进行了分析，这表明ERBB2信号传导对于白血病细胞生长/存活可能很重要。针对ERBB2的药物的初步研究表明该途径具有功能作用。综上所述，我们的初步表明，基于CRG的白血病分析可能是确定白血病中心的机制的强大手段。 根据迄今为止的发现，我们假设CRG在我们的小鼠模型系统中高度富集了白血病的关键调节剂。此外，我们建议研究此类基因是否对原发性人类爆炸危机CML的生长也很重要。对于小鼠和人类研究，我们的重点将是对白血病干细胞种群中CRG的分析。综上所述，这些研究将为介导白血病疾病的途径和过程提供全面的理解。