Activation of BCL-2 in Hematologic Malgnancies

滤泡性淋巴瘤的特征是 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 等位基因高水平表达，并且 正常的等位基因是沉默的。 Bcl-2 水平升高有助于对化疗药物产生耐药性， 滤泡性淋巴瘤很少能治愈。我们研究了易位的 bcl-2 基因是如何发生的 受 IgH 基因座解除调控，并已在 bcl-2 启动子和 3' IgH 中鉴定出调控位点 增强剂。这些位点的参与已在易位的游离模型中得到证实。 在本提案中，我们将基于之前的结果，使用解除管制的 bcl-2 小鼠模型 由 IgH 3' 增强子诱导的表达（IgH-bcl-2 小鼠）。我们的研究提供了对 涉及 bcl-2 表达失调的机制，并且还提供了证据表明 bcl-2 表达的激活比之前想象的更复杂。根据这些结果，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其中一个如何 推动者影响对方。此外，我们的数据表明，虽然需要 IgH 增强剂 对于 bcl-2 表达的放松管制，它们是不够的，并且在 B细胞的转化过程。我们的研究将针对基因组中的 bcl-2 基因进行 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 增强剂一起。此外，我们将描述 lgH-bcl-2 小鼠中发生的淋巴瘤的特征， 将它们与人类滤泡性淋巴瘤进行比较。 1. 表征 bcl-2 P2 启动子转录缺失所涉及的机制 缺乏 IgH 增强剂。 2. lgH-bcl-2 小鼠 B 细胞中 bcl-2 失调的分子机制表征 进一步阐明 t(14;18) 淋巴瘤中 bcl-2 失调的机制。 3.利用lgH-bcl-2小鼠开发t(14;18)淋巴瘤的临床前模型。 相关性：我们正在研究 B 淋巴细胞恶性肿瘤，以了解遗传异常的作用 涉及 bcl-2 基因，该基因编码一种延长恶性细胞存活时间的蛋白质。我们的 研究旨在确定 bcl-2 基因如何高水平表达并开发 人类恶性肿瘤（滤泡性淋巴瘤）的小鼠模型。这些研究将提供新信息 可以用来治疗人类的疾病。

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.