Role of the BCL 6 Proto Oncogene in B Cell Lymphomas

该项目的主要目的是了解BCL-6基因是如何调控的，以及它的功能如何。 与IL-6/STAT 3途径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编码一个POZ-锌指型转录抑制因子，被认为抑制转录 通过募集辅阻遏物SMRT/NCoR/BCoR和NuRD/MTA 3在体内进行。BCL-6的组成型表达为 在许多弥漫性大细胞淋巴瘤（DLBCL）中，由于基因改变， 控制BCL-6转录的自身调节机制。在正常淋巴系统中，高水平的BCL-6 在生发中心（GC）内的B细胞中特异性发现一种蛋白质，BCL-6的功能对于GC至关重要 阵我们最近的工作表明BCL-6的自动调节作用于SMRT/NCoR/BCoR-和 NuRD/MTA 3独立方式。因此，在目标1中，我们计划表征特定的染色质变化 参与BCL-6自身调节，并鉴定BCL-6蛋白用于调节其 自己的转录。我们最近的研究还发现了一系列非常新颖的发现，表明BCL 6是一种 STATS表达/活化的强有力抑制剂，并且STATS在活化的细胞中组成性活化。 B细胞样DLBCL（ABC-DLBCL）是细胞增殖和存活所必需的。因此，目标2中的实验 目的是研究浆细胞中BCL 6和STATS之间的功能关系， 分化，确定ABC-DLBCL中组成性STATS激活的原因，并研究ABC-DLBCL中STATS的表达。 组成型激活的STATS在体内的致瘤潜力。由于ABC-DLBCL通常与 治疗结果不佳，我们还计划进行合作研究，以评估 原发性DLBCL中的STATS活化作为单一标志物或与BCL 6组合。我们的研究 应该提供关于BCL 6反式阻遏机制的新方面的有价值的信息， 更重要的是，进一步了解BCL 6和STATS在遗传学中所起的作用， B细胞淋巴瘤生物学。

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.