Role of CXCR4 in immunoglobulin light chain recombination

项目摘要 在B淋巴细胞生成过程中存在着随机免疫球蛋白基因的交替和互斥状态 重组和细胞增殖与选择。在成功重排IG重链后 基因，IGµ与替代轻链（SLC）配对形成前BCR，其表达与 克隆性大前B细胞扩增。然而，在随后的发育阶段，小的前B细胞必须完全 在启动IG轻链（IgL）基因重组之前退出细胞周期。如果不这样做，基因组就会不稳定 和白血病转化。我们实验室和其他实验室的工作表明，IL-7 R驱动细胞增殖， 而pre-BCR似乎主要负责IgL重组。然而，有一个明显的矛盾， IgL重排发生在小的前B细胞中，其中同时存在SLC的强烈抑制。那里 有两种可能前BCR可以在大的前B细胞中启动复杂的发育程序， 在小的前B细胞中执行。或者，可能有其他受体或机制协调IgL 链重组我们现在证明，在小的前B细胞中上调的CXCR 4， 传递信号打开Igk进行重组。事实上，它是CXCR 4介导的ERK激活，而不是逃避 IL-7，也不表达介导晚期B淋巴细胞生成的前BCR。这些和其他数据表明， 一种新的B淋巴细胞生成模型，其中通过三种受体，IL-7 R，前BCR和 CXCR 4，协调关键的细胞命运决定。我们建议在以下具体目标中测试这种模式： 目标1.识别前BCR下游的特定信号通路。 目的2：确定CXCR 4信号如何与pre-BCR/IL-7 Resc整合以驱动Igk重组。 目标3.确定CXCR 4如何调节受体编辑。

PROJECT SUMMARY In B lymphopoiesis there are alternating and mutually exclusive state of stochastic immunoglobulin gene recombination and cell proliferation with selection. Following successful rearrangement of the Ig heavy chain gene, Igµ pairs with surrogate light chain (SLC) to form the pre-BCR, expression of which is associated with clonal large pre-B cell expansion. However, at the subsequent developmental stage, small pre-B cells must fully exit cell cycle before initiating Ig light chain (IgL) gene recombination. Failure to do so risks genomic instability and leukemic transformation. Work from our lab and others has demonstrated that the IL-7R drives proliferation while the pre-BCR primarily appears tasked with IgL recombination. However, there is an apparent paradox in that IgL rearrangement occurs in small pre-B cells in which there is concurrent strong repression of SLC. There are two possibilities. The pre-BCR could initiate a complex developmental program in large pre-B cells that is executed in small pre-B cells. Alternatively, there could be other receptors or mechanisms that orchestrate IgL chain recombination. We now demonstrate that CXCR4, which is upregulated in small pre-B cells, directly transmits signals that open Igk to recombination. Indeed, it is CXCR4-mediated ERK activation, and not escape from IL-7, nor expression of the pre-BCR, that mediates late B lymphopoiesis. These and other data suggest a new model of B lymphopoiesis in which sequential signaling through three receptors, the IL-7R, pre-BCR and CXCR4, orchestrate critical cell fate decisions. We propose to test this mode in the following Specific Aims: Aim 1. Identify the signaling pathways specifically downstream of the pre-BCR. Aim 2: Determine how CXCR4 signals integrate with pre-BCR/IL-7Resc to drive Igk recombination. Aim 3. Determine how CXCR4 regulates receptor editing.