Molecular basis of the requirements for IRF4 and IRF8 in pre-B cell development

描述（由申请人提供）：B淋巴细胞通过依赖于一系列复杂调节分子的协调活性的过程从祖细胞发育而来。这种高度调节的发育过程的中断通常导致异常的B细胞发育，从而导致诸如自身免疫、白血病和淋巴瘤的疾病。因此，提高对控制B细胞发育的分子机制的理解可以为B细胞衍生疾病的发病机制提供新的见解。缺乏免疫系统特异性转录因子IRF 4和IRF 8（IRF 4，8）的小鼠在前B细胞发育中具有严重缺陷。我们的长期目标是了解IRF如何协调B细胞的发育4，8。本申请的目的是阐明IRF 4，8控制前B细胞发育的分子机制。我们将检验IRF 4，8是前BCR启动的信号通路的核效应子的假设，该信号通路限制前B细胞扩增并促进前B细胞分化。基于我们先前的研究和初步的发现，我们提出了这个假设，这些发现表明IRF 4，8的表达受前BCR信号的调节，并且在IRF 4，8缺失的情况下，前B细胞显示出退出细胞周期和重排轻链的缺陷。该提案包括以下具体目标： 目标1。阐明IRF 4，8负调控前B细胞扩增的分子机制。我们将检验IRF 4，8作为替代轻链Vpre-B和Vpreda 5表达的负调节剂的功能，以及IRF 4，8在关闭前B细胞对IL-7的应答中是必需的这一假设。 目标2。确定IRF 4，8控制前B细胞分化的分子机制。由于轻链重排和转录在IRF 4，8-/-前B细胞中严重受损，我们将检验IRF 4，8控制轻链基因座对V（D）J重组酶的可及性的假设。 目标3。确定IRF 4、8为前BCR信号通路的核效应子。在缺乏IRF的情况下4，8，前B细胞发育似乎是正常的，但前B细胞发育被阻断。我们假设IRF 4，8的表达在前B阶段由前BCR通过Blnk/Btk介导的信号传导诱导。

DESCRIPTION (provided by applicant): B lymphocyte develops from progenitor cell through a process that is dependent on the coordinated activity of a complex array of regulatory molecules. The disruption of this highly regulated developmental process often leads to abnormal B cell development, resulting in diseases such as autoimmunity, leukemia and lymphoma. Therefore, improved understanding of the molecular mechanisms that control B cell development could provide novel insights into pathogenesis of B cell-derived diseases. Mice lacking immune system specific transcription factors IRF4 and IRF8 (IRF4,8) have a profound defect in pre-B cell development. Our long-term goal is to understand how B cell development is orchestrated by IRF4,8. The objective for this application is to elucidate the molecular mechanisms by which IRF4,8 control pre-B cell development. We will test the hypothesis that IRF4,8 are the nuclear effectors of a pre-BCR initiated signaling pathway that limits pre-B cell expansion and promotes pre-B cell differentiation. We have formulated this hypothesis based on our previous study and preliminary findings, which suggest that IRF4,8 expression are regulated by pre-BCR signaling and in the absence of IRF4,8, pre-B cells show defects in exiting from cell cycle and in rearranging light chain. The proposal includes the following specific aims: Aim #1. To elucidate the molecular mechanisms by which IRF4,8 negatively regulate pre-B cell expansion. We will test the hypothesis that IRF4,8 function as negative regulators of the expression of surrogate light chain Vpre-B and lambda5, and that IRF4,8 are essential in shutting down pre-B cell response to IL-7. Aim #2. To determine the molecular mechanisms by which IRF4,8 control pre-B cell differentiation. Because light chain rearrangement and transcription are severely impaired in IRF4,8-/- pre-B cells, we will test the hypothesis that IRF4,8 control the accessibility of light chain loci to V(D)J recombinase. Aim #3. To establish IRF4,8 as the nuclear effectors of pre-BCR signaling pathway. In the absence of IRF4,8, pro-B cell development appears to be normal but pre-B cell development is blocked. We hypothesize that expression of IRF4,8 is induced at the pre-B stage by pre-BCR though Blnk/Btk-mediated signaling.