Role of the BCL 6 Proto Oncogene in B Cell Lymphomas

这个项目的主要目标是了解bcl6基因是如何调控的，以及它的功能是如何的。 与IL-6/STAT3通路的相互作用可能有助于其在正常B细胞和B细胞淋巴瘤中的作用。 BCL-6编码一种被认为抑制转录的POZ-锌指型转录抑制子 在体内通过招募辅抑制子SMRT/NCoR/BCOR和NuRD/MTA3。BCL-6在结构上表达于 许多弥漫性大细胞淋巴瘤(DLBCL)由于基因改变而导致的高水平 调控bcl6转录的自身调节机制。在正常淋巴系统中，高水平的bcl6 蛋白质特异性存在于生发中心(GC)内的B细胞中，BCL-6的功能在GC中起关键作用 队形。我们最近的工作表明，BCL-6自动调节在SMRT/NCoR/BCOR-和 NuRD/MTA3独立的方式。因此，在目标1中，我们计划描述特定的染色质变化 参与bcl6自身调节，并确定bcl6蛋白使用的新的辅阻遏子来调节其 自己的抄本。我们最近的研究还发现了一组非常新的发现，表明BCL6是一种 STATS表达/激活的强大抑制者，且STATS在被激活的 B细胞类似DLBCL(ABC-DLBCL)，是细胞增殖和生存所必需的。因此，目标2中的实验 旨在描述浆细胞中BCL6和STATS之间的功能关系 分化，确定ABC-DLBCL中STATS结构性激活的原因，并研究 体内结构性激活的STATS的致瘤潜能。由于ABC-DLBCL经常与 治疗结果不佳，我们还计划进行合作研究，以评估 STATS在原发DLBCL中作为单一标志物或与BCL6联合激活。我们的研究 应该提供关于bcl6的S反转录抑制机制的一个新方面的有价值的信息 更重要的是，加深了我们对BCL6和STATS在遗传学和 B细胞淋巴瘤的生物学。

The main objective of this project is to understand how the BCL-6 gene is regulated and how its functional interaction with the IL-6/STAT3 pathway may contribute to its role in normal B cells and B cell lymphomas. BCL-6 encodes a POZ-zinc finger type transcription represser that has been thought to repress transcription in vivo by recruiting corepressors SMRT/NCoR/BCoR and NuRD/MTA3. BCL-6 is constitutively expressed at high levels in many diffuse large cell lymphomas (DLBCL) due to genetic alterations that override a negative autoregulatory mechanism governing BCL-6 transcription. In the normal lymphoid system, high level BCL-6 protein is specifically found in B cells within the germinal centers (GC) and BCL-6 function is critical for GC formation. Our recent work indicates that BCL-6 autoregulation works in a SMRT/NCoR/BCoR-and NuRD/MTA3 independent manner. Therefore in Aim 1, we plan to characterize specific chromatin changes involved in BCL-6 autoregulation and identify the novel corepressor used by the BCL-6 protein to regulate its own transcription. Our recent study also uncovered a set of very novel findings indicating that BCL6 is a powerful inhibitor of STATS expression/activation, and that STATS is constitutively activated in the activated B cell like DLBCL (ABC-DLBCL) and required for cell proliferation and survival. Thus, experiments in Aim 2 are designed to characterize the functional relationship between BCL6 and STATS in plasma cell differentiation, determine the cause of constitutive STATS activation in ABC-DLBCL, and study the tumorigenic potential of a constitutively activated STATS in vivo. Since ABC-DLBCL is often associated with poor treatment outcome, we also plan to pursue collaborative studies to evaluate the prognostic value of STATS activation in primary DLBCL either as a single marker or in combination with BCL6. Our studies should provide valuable information regarding a novel aspect of BCL6's transrepression mechanism and more importantly, further our understanding of the roles played by BCL6 and STATS in the genetics and biology of B cell lymphomas.