Oncogene Cooperativity in Leukemia Stem Cells

白血病干细胞中的癌基因协同作用

基本信息

批准号：
8446325
负责人：
Craig T. Jordan
金额：
$ 30.14万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446325
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 Physiological Pilot Projects Process Property Regimen Reporting Resistance Role SERPINB2 gene Signal Transduction Specimen System 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 novel novel strategies novel therapeutics public health relevance research study response restoration small hairpin RNA stem stem cell biology stem cell population tool tumor tumorigenesis

项目摘要

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系白血病干细胞（LSC）致癌转化的分子参数。这一目标基于现有关于 LSC 的作用和生物学特性的压倒性证据。大量研究已经证明 LSCs 在原代人体组织和小鼠模型系统中的存在。这种生物学上独特的亚群是白血病疾病的发生和延续的原因。此外，LSC 对传统疗法表现出显着的耐药性，因此开发新的治疗方案成为重中之重。对于此应用，我们采用了一种新的策略来分析癌基因协同性，作为阐明对恶性肿瘤最重要的基因/途径的手段。该方法采用全局基因表达谱作为工具来识别由于共表达两个协同癌基因而协同失调的基因。先前对上皮癌模型的研究表明，这种策略非常有效，并且确实成功地产生了许多涉及肿瘤形成的新机制。我们在急变危机 CML 基因定义的小鼠模型中应用了这种方法，称为“协作反应基因”或 CRG 的识别。该系统采用 BCR/ABL 和 Nup98/HoxA9 易位产物的双重表达，之前已在几份报告中进行过表征，并具有表型定义的 LSC 群体。我们的实验已经确定了该模型中满足 CRG 标准的 72 个基因。对一种 CRG（serpinB2）的初步研究表明该基因在体内白血病细胞生长中发挥重要作用。此外，使用计算方法对 CRG 表达谱进行了分析，这表明 ERBB2 信号传导可能对白血病细胞的生长/存活很重要。针对 ERBB2 的药物的初步研究表明了该通路的功能作用。综上所述，我们的初步结果表明，基于 CRG 的白血病分析可能是识别白血病发生的核心机制的有力手段。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白血病发生的关键调节因子。此外，我们建议研究这些基因是否对于原发性人类急变期 CML 的生长也很重要。对于小鼠和人类研究，我们的重点是分析白血病干细胞群中的 CRG。总而言之，这些研究将提供对介导白血病的途径和过程的全面了解。