IRF4 Functions as a Negative Regulator of Notch Signaling in the Development of M

描述（由申请方提供）：免疫球蛋白重链和轻链基因成功重排后，B淋巴细胞离开骨髓并进入次级淋巴器官，在那里它们进一步分化为边缘区B细胞（MZ B）或滤泡B细胞（FO B），这两种成熟B细胞亚群在表面表型、解剖位置和免疫功能方面不同。虽然B细胞产生率、BCR特异性和BCR信号强度都与MZ B细胞的发育有关，但控制MZ B细胞发育的分子机制尚未完全阐明。Notch信号传导对于MZ B细胞发育至关重要。遗传分析表明，当小鼠中Notch 2或Notch信号下游的信号分子缺失时，MZ B细胞发育严重受损。Notch信号在MZ B细胞及其前体细胞中异常活跃，但在FO B细胞中不活跃。表达组成型活性Notch转基因的小鼠具有显著扩增的MZ B细胞群。最近的全基因组序列分析显示，Notch 2和Notch 1在MZ B细胞来源的淋巴瘤中频繁突变，表明过度活跃的Notch信号传导对于肿瘤发生过程至关重要。已经显示Notch信号传导可以在其他组织中在细胞内调节。然而，Notch信号传导如何在MZ B细胞中调节仍然知之甚少。干扰素调节因子4（Interferon Regulatory Factor 4，IRF 4）是IRF家族转录因子中的一员。我们和其他人以前的工作表明，IRF 4对B细胞的发育和功能至关重要。然而，IRF 4在MZ B细胞发育中的作用仍不清楚。在这个建议中，我们将测试的假设，IRF 4是一个负调控Notch信号的功能，以限制MZ B细胞的发展。我们将通过以下具体目标来验证我们的假设：目标#1是确定IRF 4对Notch信号传导和MZ B细胞发育的影响;目标#2是阐明IRF 4减弱Notch信号传导的分子机制。本研究的成功完成将为IRF 4在MZ B细胞发生发展中的作用以及在MZ B细胞源性淋巴瘤发病机制中的作用提供分子基础。

DESCRIPTION (provided by applicant): After successful rearrangement of immunoglobulin heavy and light chain genes, B lymphocytes exit the bone marrow and enter the secondary lymphoid organs where they further differentiate into either marginal zone B cells (MZ B) or follicular B cells (FO B) cells, two mature B cell subsets that differ in surface phenotype, anatomic location and immunological function. Although B cell production rate, BCR specificity and BCR signaling strength have all been linked to development of MZ B cells, the molecular mechanism that controls MZ B cells development has not been fully elucidated. Notch signaling is critical for MZ B cell development. Genetic analysis has shown that MZ B cell development is severely impaired when either Notch2 or signaling molecules downstream of Notch signaling are deleted in mice. Notch signaling is found to be hyperactive in the MZ B cells and their precursors but not in the FO B cells. Mice expressing a constitutive active Notch transgene have a dramatically expanded MZ B cell population. Recent whole genome sequence analysis reveals that Notch2 and Notch1 are frequently mutated in MZ B cell derived lymphoma, indicating that hyperactive Notch signaling is critical for the tumorigenesis process. It has been shown that Notch signaling can be modulated intracellularly in other tissues. However, how Notch signaling is modulated in MZ B cells remains poorly understood. Interferon regulatory factor 4 (IRF4) is a member of IRF family of transcription factor. Previous works from us and others have shown that IRF4 is critical for B cell development and function. However, the role of IRF4 in MZ B cell development remains unclear. In this proposal, we will test the hypothesis that IRF4 is a negative regulator of Notch signaling that functions to limit MZ B cell development. We will test our hypotheses through the following specific aims: aim #1 is to determine the effect of IRF4 on Notch signaling and development of MZ B cells; and aim #2 is to elucidate the molecular mechanism by which IRF4 attenuates Notch signaling. Successful completion of this proposal could provide the molecular basis on the role of IRF4 not only in MZ B development but could also on the pathogenesis of MZ B cell derived lymphoma.