Activation of BCL-2 in Hematologic Malgnancies

BCL-2 在血液恶性肿瘤中的激活

• 批准号: 7483462
• 负责人: LINDA M BOXER
• 金额: $ 29.49万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483462
• 关键词: Alleles; B-Lymphocytes; BCL2 gene; Cell Line; Cells; Chromosome Structures; Code; Complex; Data; Development; Disease; Enhancers; Follicular Lymphoma; Genetic Transcription; Genomics; Growth; Human; IGH@ gene cluster; Immunoglobulin Genes; Immunoglobulins; Investigation; Link; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Molecular Abnormality; Mus; Mutate; Mutation; Population; Pre-Clinical Model; Premalignant; Process; Proteins; Regulation; Resistance; Role; Sampling; Site; Thinking; base; cancer cell; cell transformation; chemotherapeutic agent; design; insight; mouse model; prevent; promoter; research study

Follicular lymphoma is characterized by the t(14;18) translocation, which links the bcl-2 gene with the immunoglobulin heavy chain gene (IgH). The translocated bcl-2 allele is expressed at high levels, and the normal allele is silent. The increased levels of Bcl-2 contribute to resistance to chemotherapeutic agents, and follicular lymphoma is rarely cured. We have investigated how the translocated bcl-2 gene is deregulated by the IgH locus and have identified regulatory sites in the bcl-2 promoter and in the 3' IgH enhancers. The involvement of these sites has been confirmed in an episomal model of the translocation. In this proposal, we will build upon our previous results using a murine model of deregulated bcl-2 expression induced by the IgH 3' enhancers (lgH-bcl-2 mice). Our studies have provided insight into the mechanisms involved in the deregulation of bcl-2 expression and have also provided evidence that the activation of bcl-2 expression is more complex than previously thought. Based on these results, we propose to more closely examine the regulation of the two bcl-2 promoters in normal B cells and study how one promoter influences the other. In addition, our data demonstrate that while the IgH enhancers are required for the deregulation of bcl-2 expression, they are not sufficient, and that additional changes occur during the transformation process of the B cell. Our investigations will be performed on the bcl-2 gene in the genomic context so that we can study the chromosomal structure at the bcl-2 promoter and define the interactions with the IgH enhancers. Additionally, we will characterize the lymphomas that develop in lgH-bcl-2 mice and compare them to human follicular lymphomas. 1. Characterization of the mechanisms involved in the lack of transcription from the bcl-2 P2 promoter in the absence of the IgH enhancers. 2. Characterization of the molecular mechanisms of bcl-2 deregulation in B cells from lgH-bcl-2 mice to further clarify the mechanisms of bcl-2 deregulation in t(14;18) lymphomas. 3. Development of a preclinical model for t(14;18) lymphomas utilizing the lgH-bcl-2 mice. Relevance: We are studying a malignancy of B lymphocytes to understand the role of a genetic abnormality involving the bcl-2 gene, which codes for a protein that extends the survival of the malignant cells. Our investigations are designed to determine how the bcl-2 gene is expressed at high levels and to develop a mouse model for the human malignancy (follicular lymphoma). These studies will provide new information that can be used to treat the disease in humans.

卵泡淋巴瘤的特征是T（14; 18）易位，该易位将Bcl-2基因与 免疫球蛋白重链基因（IGH）。易位的Bcl-2等位基因以高水平表示 普通等位基因是沉默的。 Bcl-2的水平升高有助于对化学治疗剂的抗性， 卵泡淋巴瘤很少治愈。我们已经研究了易位的Bcl-2基因是如何 由IGH基因座放松管制，并确定了Bcl-2启动子中的调节位点和3'igh 增强剂。这些站点的参与已在易位模型中得到证实。 在此提案中，我们将使用放松管制的Bcl-2的鼠模型以先前的结果为基础 IGH 3'增强子（LGH-BCL-2小鼠）诱导的表达。我们的研究提供了对 涉及BCL-2表达管制的机制，还提供了证据表明 Bcl-2表达的激活比以前认为的更为复杂。基于这些结果，我们建议 更仔细地检查正常B细胞​​中两个Bcl-2启动子的调节，并研究一个 发起人影响对方。此外，我们的数据表明，虽然需要增强器 为了放松Bcl-2表达，它们还不够，并且在此期间发生了其他变化 B细胞的转化过程。我们的研究将在基因组中的Bcl-2基因上进行 上下文，以便我们可以研究Bcl-2启动子处的染色体结构并定义相互作用 与IGH增强剂。此外，我们将表征在LGH-BCL-2小鼠中发育的淋巴瘤和 将它们与人卵泡淋巴瘤进行比较。 1。表征在Bcl-2 P2启动子中缺乏转录的机制 缺乏IGH增强剂。 2。表征来自LGH-BCl-2小鼠B细胞中BCl-2失调的分子机制 进一步阐明了t（14; 18）淋巴瘤中Bcl-2放松管制的机制。 3。利用LGH-BCL-2小鼠的t（14; 18）淋巴瘤的临床前模型的开发。 相关性：我们正在研究B淋巴细胞的恶性肿瘤，以了解遗传异常的作用 涉及Bcl-2基因，该基因编码为扩展恶性细胞存活的蛋白质。我们的 研究旨在确定Bcl-2基因如何在高水平上表达并开发 人类恶性肿瘤的小鼠模型（卵泡淋巴瘤）。这些研究将提供新信息 可以用来治疗人类的疾病。