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）：成熟的B细胞淋巴瘤是一组多种疾病，它们具有未能将分化过程完成为浆细胞或凋亡的特性。 PRDI-BF1及其鼠同系生Blimp-1是转录抑制剂，并充当分子转换，以使活化的B细胞成为非分裂的浆细胞或经历凋亡。在这一角色中，PRDI-BF1对于正常的体液免疫反应以及成熟的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表达或功能有助于淋巴瘤的持久性，并且旨在挽救PRDI-BF1功能的疗法可能对治疗淋巴瘤可能很重要。 PRDI-BF1的人工过表达导致多种淋巴瘤线的凋亡。此外，我们发现，我们发现用化学治疗剂（如蛋白酶体或组蛋白脱乙酰基酶抑制剂）对淋巴瘤细胞的治疗得到支持的支持，从而导致PRDI-BF1表达的早期诱导。我们最近发现了PRDI-BF1直接募集组蛋白甲基转移酶G9A以介导干扰素β的沉默。这表明染色质重塑是PRDI-BF1驱动B细胞末端分化并杀死淋巴瘤细胞的手段。将研究由PRDI-BF1在此过程中驱动的染色质重塑的影响。 PRDI-BF1在转录上受未知机制调节。这将进行调查，并将在此关键的发育时间点对转录调节提供首次详细的理解，并可能提出诱导PRDI-BF1的新途径。最后，PRDI-BF1函数需要一个高度保守的固定域，但其活性尚不清楚。我们将确定在此站点上相互作用的蛋白质，并确定其在PRDI-BF1活性中的作用。因此，该提案将对分化过程中发生的事件进行新的启示，并可能表明新目标影响淋巴瘤的生长和持久性。