PRDI-BF1 and histone methyltransferase in lymphoma

描述(申请人提供)：成熟性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及其小鼠同系物Blimp-1是转录抑制因子，可以作为分子开关将激活的B细胞转化为不分裂的浆细胞或进行凋亡。在这一作用中，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的表达或功能是导致淋巴瘤持续存在的原因，因此旨在挽救PRDI-BF1功能的治疗方法在淋巴瘤的治疗中可能是重要的。人工过表达PRDI-BF1可诱导多种淋巴瘤细胞发生凋亡。此外，我们发现，用蛋白酶体或组蛋白去乙酰酶抑制剂等化疗药物处理淋巴瘤细胞会导致PRDI-BF1表达的早期诱导，这一假设得到了支持。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细胞终末分化和杀伤淋巴瘤细胞的手段。将研究PRDI-BF1在这一过程中驱动的染色质重塑的影响。PRDI-BF1在转录水平上受未知机制调控。这将被调查，并将提供第一个详细的了解转录调控在这个关键的发展时间点，并可能提出新的途径，以诱导PRDI-BF1。最后，PRDI-BF1功能需要一个高度保守的集合型结构域，但其活性尚不清楚。我们将确定在这个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，并可能指明影响淋巴瘤生长和持久性的新靶点。

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.