The Role of CTIP in Lymphocyte Development and Lymphomagenesis

B细胞非霍奇金淋巴瘤（B-NHL）是人类第五大常见癌症。B-NHL是 以染色体易位为特征， (Ig)基因座的细胞原癌基因，导致其表达失调。这些易位经常出现在 正常B细胞增殖过程中产生的程序性DNA双链断裂（DSB）的错误修复 发展，特别是V（D）J重组和类别转换（CSR）。序列分析 正常的IG重排基因产物以及B-NHL相关的染色体易位显示， 微同源（MH）在连接处的广泛参与，表明MH介导的 正常淋巴细胞发育中的末端连接（MMEJ）以及染色体易位， 淋巴瘤形成然而，MMEJ的遗传成分和调节在很大程度上是未知的， 它们在淋巴细胞发育和淋巴瘤发生中的作用。CtBP相互作用蛋白（CtIP，也称为 RBBP 8）对于末端切除是必需的，这是暴露断裂位点侧翼的同源序列所必需的 关于MMEJ在这里，我们建议研究CtIP在致癌染色体易位中的作用， 在V（D）J重组和CSR期间由持续DSB引起的淋巴瘤发生。具体而言，目标1 我们将研究正常V（D）J重组和V（D）J重组是否需要CtIP- 介导的染色体易位和淋巴瘤发生。与其他项目合作 1（Symington），2（Gautier和Gottesman）和4（Baer）中，我们还将确定V（D）J中的CtlP函数是否 重组介导的易位涉及其与BRCA 1，CtBP和RB的相互作用，以及 PISK相关蛋白激酶的调节。在目标2中，我们将研究CtlP是否是CSR所需的- 介导的易位和B-NHL从成熟胚系中心B细胞的发展。我们还将 确定CtIP是否是MYC诱导的淋巴瘤发生所需的，以及CtIP是否足够，当去调节时， 来驱动转基因小鼠的淋巴瘤发生。后面的实验是基于我们的初步结果， 其鉴定CtIP为发育中的B细胞中c-MYC原癌基因的潜在转录靶标。 相关性（参见说明）： B细胞淋巴瘤常伴有复发性致癌染色体易位。我们建议澄清 CtIP在产生导致B细胞恶性肿瘤的致癌易位中的作用以及在Myc- 介导的淋巴瘤发生。更好地理解导致B细胞淋巴瘤的基本过程， 沿着我们将产生的新的小鼠模型，应该有助于开发更好的治疗方法。 在这个项目中与研究人员的频繁互动将大大促进我们目标的实现。

B-cell non-Hodgkin Lymphoma (B-NHL) represents the fifth most common cancer in humans. B-NHL is characterized by chromosomal translocations that juxtapose regulatory elements from the Immunoglobulin (Ig) loci to cellular proto-oncogenes causing their deregulated expression. These translocations often arise from mis-repair of programmed DNA double strand breaks (DSBs) generated during normal B cell development, specifically V(D)J recombination and Class Switch Recombination (CSR). Sequence analysis of normal Ig rearranged gene products as well as B-NHL-associated chromosomal translocations revealed extensive involvement of micro-homology (MH) at the junction, indicating an important role for MH-mediated end joining (MMEJ) in normal lymphocyte development as well as chromosomal translocations and lymphomagenesis. Yet the genetic components and the regulation ofthe MMEJ are largely unknown, as are their roles in lymphocyte development and lymphomagenesis. CtBP-interacting protein (CtlP, also called RBBP8) is essential for end-resection, necessary to expose homology sequences flanking the site of breaks for MMEJ. Here we propose to investigate the role of CtlP in oncogenic chromosomal translocations and lymphomagenesis arising from persistent DSBs during V(D)J recombination and CSR. In particular, in Aim 1 we will investigate whether CtlP is required for normal V(D)J recombination and V(D)J recombination- mediated chromosomal translocations and lymphomagenesis. In collaboration with other projects 1 (Symington), 2 (Gautier and Gottesman) and 4 (Baer), we will also determine if the function of CtlP in V(D)J recombination meditated translocations involves its interaction with BRCA1, CtBP and RB, as well as the regulation by PISK related protein kinase. In Aim 2, we will investigate whether CtlP is required for CSR- mediated translocations and the development of B-NHL from mature gemrilnal center B cells. We will also determine if CtlP is required for MYC-induced lymphomagenesis and if CtlP is sufficient, when deregulated, to drive lymphomagenesis in transgenic mice. The latter experiments are based on our preliminary results, which identify CtlP as a potential transcriptional target of the c-MYC proto-oncogene in developing B cells. RELEVANCE (See instructions): B cell lymphomas often harbrar recurrent oncogenic chromosomal translocations. We propose to elucidate the roles of CtlP in generating oncogenic translocations that lead to B cell-malignancies and in Myc- mediated lymphomagenesis. Better understanding of fundamental processes that lead to B cell lymphoma, along with the novel mouse models we will generate, should facilitate devebpment of better treatments. Frequent interaction with investigators in this program will greatly enhance the accomplishment of our goals.