PRDI-BF1 and histone methyltransferase in lymphoma

淋巴瘤中的 PRDI-BF1 和组蛋白甲基转移酶

• 批准号: 7226276
• 负责人: KENNETH Lynn WRIGHT
• 金额: $ 22.68万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-27 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226276
• 关键词: Affect; Antigens; Apoptosis; Architecture; B cell differentiation; B lymphocyte-induced maturation protein 1; B-Cell Lymphomas; B-Lymphocytes; BCL6 gene; Back; Binding; Biological; Bortezomib; Cell Death; Cell Maturation; Cell Proliferation; Cells; Chromatin Structure; Commit; Data; Development; Disease; Disruption; Event; FOXG1B gene; Failure; Family; Family member; Feeds; G9a histone methyltransferase; Gene Expression; Genes; Genetic Transcription; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Homologous Gene; Immune response; Indium; Interferon-beta; Light; Lymphoma; Lysine; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Mediator of activation protein; Methylation; Modeling; Molecular; Multiple Myeloma; Mus; Nuclear Matrix-Associated Proteins; Oncogenic; PAX5 gene; PRDM1 gene; Phenotype; Plasma Cells; Play; Process; Property; Protein Overexpression; Proteins; Recruitment Activity; Regulation; Role; Site; Stimulus; T-Lymphocyte; Time; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Activation; Transcriptional Regulation; Up-Regulation; c-myc Genes; cancer cell; cell killing; cell type; chemotherapeutic agent; chromatin remodeling; histone methyltransferase; human FOXG1B protein; in vivo; inhibitor/antagonist; multicatalytic endopeptidase complex; promoter; protein function; response; therapy design; tool

DESCRIPTION (provided by applicant): Mature B cell lymphomas are a diverse set of diseases which share the property of having failed to complete the differentiation process into plasma cells or undergo apoptosis. PRDI-BF1 and its murine homologue Blimp-1 are transcriptional repressors and act as a molecular switch to commit activated B cells to become non-dividing plasma cells or undergo apoptosis. In this role PRDI-BF1 has broad significance for normal humoral immune responses and in malignancies of mature B cells and plasma cells. We hypothesize that failure to induce PRDI-BF1 expression or function contributes to the persistence of lymphomas and as such therapies designed to rescue PRDI-BF1 function may be important in treating lymphoma. Artificial overexpression of PRDI-BF1 leads to apoptosis in multiple lymphoma lines. Furthermore the hypothesis is supported by our finding that treatment of lymphoma cells with chemotherapeutic agents such as proteasome or histone deacetylase inhibitors leads to an early induction of PRDI-BF1 expression. We have made the recent discovery that PRDI-BF1 directly recruits the histone methyltransferase G9a to mediate silencing of interferon-beta. This suggests chromatin remodeling is the means by which PRDI-BF1 drives terminal differentiation of B cells and kills lymphoma cells. The impact of chromatin remodeling driven by PRDI-BF1 in this process will be investigated. PRDI-BF1 is transcriptionally regulated by unknown mechanisms. This will be investigated and will provide the first detailed understanding of transcriptional regulation at this critical developmental time point and may suggest new avenues to induce PRDI-BF1. Finally, PRDI-BF1 function requires a highly conserved SET-like domain but its activity is unknown. We will identify the proteins interacting at this site and determine their role in PRDI-BF1 activity. Thus this proposal will shed new light on the events occurring during differentiation and may indicate new targets to affect the growth and persistence of lymphomas.

描述（由申请人提供）：成熟B细胞淋巴瘤是一种多种多样的疾病，其共同特征是未能完成向浆细胞的分化过程或发生凋亡。PRDI-BF1及其小鼠同源物Blimp-1是转录抑制因子，作为分子开关，使活化的B细胞变成不分裂的浆细胞或发生凋亡。在这一作用中，PRDI-BF1在正常的体液免疫反应以及成熟B细胞和浆细胞的恶性肿瘤中具有广泛的意义。我们假设，未能诱导PRDI-BF1表达或功能有助于淋巴瘤的持续存在，并且这些旨在恢复PRDI-BF1功能的疗法可能在治疗淋巴瘤中很重要。人工过表达PRDI-BF1可导致多种淋巴瘤细胞凋亡。此外，我们的研究结果支持了这一假设，即使用化疗药物（如蛋白酶体或组蛋白去乙酰化酶抑制剂）治疗淋巴瘤细胞可早期诱导PRDI-BF1表达。我们最近发现PRDI-BF1直接募集组蛋白甲基转移酶G9a介导干扰素- β的沉默。这表明染色质重塑是PRDI-BF1驱动B细胞终末分化和杀死淋巴瘤细胞的手段。我们将研究由PRDI-BF1驱动的染色质重塑在这一过程中的影响。PRDI-BF1受未知机制的转录调控。我们将对此进行研究，并将首次详细了解这一关键发育时间点的转录调控，并可能提出诱导PRDI-BF1的新途径。最后，PRDI-BF1功能需要一个高度保守的类似set的结构域，但其活性尚不清楚。我们将鉴定在该位点相互作用的蛋白，并确定它们在PRDI-BF1活性中的作用。因此，这一建议将揭示分化过程中发生的事件，并可能指出影响淋巴瘤生长和持续的新靶点。