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

描述（由申请人提供）：在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带B细胞（MZ B）或滤泡B细胞（FO B）细胞，这两个成熟的B细胞亚群在表面表型，解剖位置和免疫功能上不同。虽然B细胞的产生速率、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信号是mzb细胞发育的关键。遗传分析表明，当Notch2或Notch信号下游的信号分子缺失时，小鼠MZ B细胞发育严重受损。发现Notch信号在MZ B细胞及其前体中过度活跃，而在FO B细胞中则没有。表达构成型活性Notch基因的小鼠mzb细胞数量显著增加。最近的全基因组序列分析显示，Notch2和Notch1在MZ B细胞源性淋巴瘤中经常发生突变，表明过度活跃的Notch信号在肿瘤发生过程中至关重要。研究表明，Notch信号可以在其他组织的细胞内被调节。然而，Notch信号如何在MZ B细胞中被调节仍然知之甚少。干扰素调节因子4 （IRF4）是IRF转录因子家族的成员。我们和其他人之前的研究表明，IRF4对B细胞的发育和功能至关重要。然而，IRF4在MZ B细胞发育中的作用尚不清楚。在本提案中，我们将验证IRF4是Notch信号的负调节因子，其功能是限制MZ B细胞的发育。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IRF4对Notch信号传导和MZ B细胞发育的影响；目的2是阐明IRF4减弱Notch信号的分子机制。该研究的成功完成不仅为IRF4在MZ B细胞性淋巴瘤的发生发展中所起的作用提供了分子基础，也为其在MZ B细胞性淋巴瘤的发病机制提供了理论依据。

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.