Role of the BCL 6 Proto Oncogene in B Cell Lymphomas

描述（由申请人提供）：本项目的主要目的是了解BCL-6基因是如何调节的，以及其与IL-6/STAT 3通路的功能相互作用如何有助于其在正常B细胞和B细胞淋巴瘤中的作用。BCL-6编码一种POZ-锌指型转录抑制因子，被认为通过募集辅抑制因子SMRT/NCoR/BCoR和NuRD/MTA 3来抑制体内转录。BCL-6在许多弥漫性大细胞淋巴瘤（DLBCL）中以高水平组成性表达，这是由于基因改变超越了控制BCL-6转录的负性自身调节机制。在正常淋巴系统中，高水平的BCL-6蛋白特异性地存在于生发中心（GC）内的B细胞中，并且BCL-6功能对于GC形成是关键的。我们最近的工作表明，BCL-6自动调节以SMRT/NCoR/BCoR和NuRD/MTA 3独立的方式起作用。因此，在目标1中，我们计划表征BCL-6自身调节中涉及的特定染色质变化，并鉴定BCL-6蛋白用于调节其自身转录的新型辅阻遏物。我们最近的研究还发现了一组非常新颖的发现，表明BCL 6是STAT 3表达/活化的强效抑制剂，并且STAT 3在活化的B细胞如DLBCL（ABC-DLBCL）中组成性活化，并且是细胞增殖和存活所需的。因此，目的2中的实验被设计为表征浆细胞分化中BCL 6和STAT 3之间的功能关系，确定ABC-DLBCL中组成型STAT 3活化的原因，并研究组成型活化的STAT 3在体内的致瘤潜力。由于ABC-DLBCL通常与不良治疗结果相关，我们还计划进行合作研究，以评估STAT 3激活作为单一标志物或与BCL 6联合使用在原发性DLBCL中的预后价值。我们的研究将为BCL 6的反式抑制机制提供有价值的信息，更重要的是，进一步了解BCL 6和STAT 3在B细胞淋巴瘤的遗传学和生物学中所起的作用。

DESCRIPTION (provided by applicant): 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 repressor 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 STAT3 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 STAT3 in plasma cell differentiation, determine the cause of constitutive STAT3 activation in ABC-DLBCL, and study the tumorigenic potential of a constitutively activated STAT3 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 STAT3 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 STAT3 in the genetics and biology of B cell lymphomas.