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: 6906698
• 负责人: KENNETH Lynn WRIGHT
• 金额: $ 23.92万
• 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/6906698
• 关键词: B cell lymphoma; antineoplastics; apoptosis; cell differentiation; cell line; chromatin; chromatin immunoprecipitation; clinical research; enzyme inhibitors; gene induction /repression; genetic promoter element; histones; human tissue; methyltransferase; multiple myeloma; neoplastic process; nuclear proteins; protein biosynthesis; protein protein interaction; protein structure function; small interfering RNA; transcription factor

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细胞淋巴瘤是一组不同的疾病，其共同特征是未能完成向浆细胞的分化过程或经历细胞凋亡。 PRDI-BF1 及其小鼠同源物 Blimp-1 是转录抑制因子，并充当分子开关，使活化的 B 细胞变成不分裂的浆细胞或经历凋亡。在这个角色中，PRDI-BF1 对于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具有广泛的意义。我们假设未能诱导 PRDI-BF1 表达或功能会导致淋巴瘤的持续存在，因此旨在挽救 PRDI-BF1 功能的疗法可能对治疗淋巴瘤很重要。 PRDI-BF1 的人工过度表达会导致多种淋巴瘤系细胞凋亡。此外，我们的发现也支持了这一假设，即用蛋白酶体或组蛋白脱乙酰酶抑制剂等化疗药物治疗淋巴瘤细胞会导致早期诱导 PRDI-BF1 表达。我们最近发现PRDI-BF1直接招募组蛋白甲基转移酶G9a来介导干扰素β的沉默。这表明染色质重塑是 PRDI-BF1 驱动 B 细胞终末分化并杀死淋巴瘤细胞的方式。将研究在此过程中 PRDI-BF1 驱动的染色质重塑的影响。 PRDI-BF1 的转录调节机制未知。我们将对此进行研究，并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 功能需要高度保守的 SET 样结构域，但其活性未知。我们将鉴定在此位点相互作用的蛋白质并确定它们在 PRDI-BF1 活性中的作用。因此，这一提议将为分化过程中发生的事件提供新的线索，并可能表明影响淋巴瘤生长和持续存在的新靶点。