Activation of BCL-2 in Hematologic Malignancies

BCL-2 在血液系统恶性肿瘤中的激活

• 批准号: 8288655
• 负责人: LINDA M BOXER
• 金额: $ 28.18万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288655
• 关键词: Alleles; B-Lymphocytes; BCL1 Oncogene; BCL2 gene; Cell Line; Cells; Chromosome Structures; Code; Complex; Data; Development; Disease; Enhancers; Follicular Lymphoma; Genetic Transcription; Genomics; Growth; Hematologic Neoplasms; Human; IGH@ gene cluster; Investigation; Link; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Abnormality; Mus; Mutate; Mutation; Population; Pre-Clinical Model; Premalignant; Process; Proteins; Regulation; Resistance; Role; Sampling; Site; Transgenic Mice; base; cancer cell; cell transformation; chemotherapeutic agent; design; insight; mouse model; prevent; promoter; research study

Project Summary 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 (IgH-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 IgH-bcl-2 mice and compare them to human follicular lymphomas. Information that we gain from the studies on mechanisms involved in bcl-2 deregulation will be utilized to interfere with bcl-2 expression in the IgH-bcl-2 mice as a method to prevent or treat the 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 IgH-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 IgH-bcl-2 mice. Project Narrative 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.

项目摘要 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水平的升高有助于对化学治疗剂的抵抗力，并且 卵泡淋巴瘤很少治愈。我们已经研究了如何通过 IGH基因座并已经确定了Bcl-2启动子和3'IGH增强子中的调节位置。这 这些站点的参与已在易位模型中得到证实。在这个建议中，我们 将使用由IGH 3'引起的放松管制的Bcl-2表达的鼠模型以我们先前的结果为基础 增强剂（IGH-BCL-2小鼠）。我们的研究提供了对涉及的机制的见解 Bcl-2表达的放松管制，还提供了Bcl-2表达激活的证据是 比以前想象的更复杂。基于这些结果，我们建议更仔细地检查 调节正常B细胞​​中两个Bcl-2启动子的调节，并研究一个启动子如何影响另一种启动子。在 此外，我们的数据表明，虽然IGH增强剂是放松管制的bcl-2 表达，它们还不够，并且在转换过程中发生其他变化 B单元。我们的研究将在基因组环境中对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与IGH增强子的相互作用。此外， 我们将表征在IGH-BCL-2小鼠中发育的淋巴瘤，并将其与人卵泡进行比较 淋巴瘤。我们从涉及Bcl-2放松管制的机制的研究中获得的信息将是 用于干扰IGH-BCL-2小鼠中Bcl-2的表达，以预防或治疗淋巴瘤。 1。表征在Bcl-2 P2启动子中缺乏转录的机制的表征 IGH增强剂的缺失。 2。表征来自IGH-BCl-2小鼠的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IGH-BCL-2小鼠的t（14; 18）淋巴瘤的临床前模型的开发。项目叙述 我们正在研究B淋巴细胞的恶性肿瘤，以了解涉及遗传异常的作用 Bcl-2基因，该基因编码扩展恶性细胞存活的蛋白质。我们的调查是 旨在确定Bcl-2基因如何在高水平上表达，并为 人类恶性肿瘤（卵泡淋巴瘤）。这些研究将提供可用于治疗的新信息 人类疾病。

项目成果

Functional long-range interactions of the IgH 3' enhancers with the bcl-2 promoter region in t(14;18) lymphoma cells.

• DOI: 10.1038/onc.2008.286
• 发表时间: 2008-12-04
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Duan, H.;Xiang, H.;Ma, L.;Boxer, L. M.
• 通讯作者: Boxer, L. M.

Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma.

滤泡性淋巴瘤和转化性淋巴瘤中 bcl-2 和 c-myc 转录控制的分子机制。

• 发表时间: 2001
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Arcinas,M;Heckman,CA;Mehew,JW;Boxer,LM
• 通讯作者: Boxer,LM

The immunoglobulin heavy chain gene 3' enhancers induce Bcl2 deregulation and lymphomagenesis in murine B cells.

• DOI: 10.1038/leu.2011.115
• 发表时间: 2011-09
• 期刊: Leukemia
• 影响因子: 11.4

Critical elements of the immunoglobulin heavy chain gene enhancers for deregulated expression of bcl-2.

免疫球蛋白重链基因增强子的关键元件，用于解除 bcl-2 的表达调控。

• 发表时间: 2003
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Heckman,CarolineA;Cao,Thai;Somsouk,Lina;Duan,Hong;Mehew,JohnW;Zhang,Chun-yi;Boxer,LindaM
• 通讯作者: Boxer,LindaM