Activation of BCL-2 in Hematologic Malgnancies

滤泡性淋巴瘤的特征是t（14;18）易位，它将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达， 正常等位基因是沉默的。Bcl-2水平的增加有助于对化疗剂的抗性， 滤泡性淋巴瘤是很少治愈。我们已经研究了bcl-2基因易位是如何在 在bcl-2启动子和3' IgH基因座中鉴定了调控位点， 增强剂。这些位点的参与已经在易位的附加型模型中得到证实。 在这个建议中，我们将建立在我们以前的结果，使用一个小鼠模型的失调bcl-2 通过IgH 3'增强子诱导的表达（IgH-bcl-2小鼠）。我们的研究提供了深入了解 bcl-2表达失调的机制，也提供了证据表明， Bcl-2表达的激活比以前认为的更复杂。基于这些结果，我们建议 为了更仔细地检查正常B细胞中两个bcl-2启动子的调节， 推动者影响另一方。此外，我们的数据表明，虽然需要IgH增强剂， 对于bcl-2表达的失调，它们是不够的，并且额外的变化发生在 B细胞的转化过程。我们的研究将在基因组中的bcl-2基因进行。 这样我们就可以研究bcl-2启动子的染色体结构并确定相互作用 免疫球蛋白H增强剂此外，我们将描述lgH-bcl-2小鼠中发生的淋巴瘤， 与人类滤泡性淋巴瘤进行比较。 1.在细胞中缺乏bcl-2 P2启动子转录的机制的表征 不存在IgH增强子。 2. lgH-bcl-2小鼠B细胞中bcl-2失调的分子机制 进一步阐明t（14;18）淋巴瘤bcl-2表达失调的机制。 3.利用lgH-bcl-2小鼠建立t（14;18）淋巴瘤临床前模型 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 它涉及bcl-2基因，该基因编码一种延长恶性细胞存活的蛋白质。我们 研究的目的是确定bcl-2基因是如何在高水平表达的， 人恶性肿瘤（滤泡性淋巴瘤）的小鼠模型。这些研究将提供新的信息 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.