PRDI-BF1 and histone methyltransferase in lymphoma

描述（由申请人提供）： 成熟B细胞淋巴瘤是一组不同的疾病，其共有未能完成向浆细胞的分化过程或经历细胞凋亡的性质。PRDI-BF 1及其鼠同源物Blimp-1是转录抑制因子，并作为分子开关使活化的B细胞变成非分裂浆细胞或经历细胞凋亡。在这种作用中，PRDI-BF 1对正常体液免疫应答和成熟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-BF 1表达或功能有助于淋巴瘤的持续存在，因此设计用于挽救PRDI-BF 1功能的治疗在治疗淋巴瘤中可能是重要的。PRDI-BF 1的人工过表达导致多个淋巴瘤系的细胞凋亡此外，我们发现用化疗剂如蛋白酶体或组蛋白去乙酰化酶抑制剂治疗淋巴瘤细胞导致PRDI-BF 1表达的早期诱导，这支持了该假设。我们最近发现PRDI-BF 1直接招募组蛋白甲基转移酶G9 a介导干扰素β的沉默。这表明染色质重塑是PRDI-BF 1驱动B细胞终末分化并杀死淋巴瘤细胞的手段。将研究PRDI-BF 1在此过程中驱动的染色质重塑的影响。PRDI-BF 1的转录调控机制尚不清楚。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-BF 1。最后，PRDI-BF 1功能需要高度保守的SET样结构域，但其活性尚不清楚。我们将确定在这个网站上相互作用的蛋白质，并确定其在PRDI-BF 1活性的作用。因此，这一建议将揭示分化过程中发生的事件，并可能表明新的目标，以影响淋巴瘤的生长和持久性。

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.