The Role of NF-kB in B-Cell Differentiation and Lymphomagenesis

描述（由申请人提供）：本研究计划旨在阐明核因子-？B (NF - ?B)转录因子复合物有助于成熟B淋巴细胞的致癌转化。大多数B细胞癌起源于抗原活化的成熟B细胞，这些细胞经过生发中心（GC）反应产生记忆B细胞和浆细胞，并且几种淋巴瘤亚型的发展与记忆B细胞或浆细胞前体的致癌转化有关。值得注意的是，这些肿瘤经常携带NF-？B通路成分导致NF-？B信号，从而识别NF-？B在GC-淋巴瘤形成中起关键作用。这些观察结果强调了阐明NF-？B有助于肿瘤前体细胞的转化。NF - ?B的激活可通过两种不同的途径发生，规范途径和替代途径，由特异性NF-？B亚基。我们已经获得了初步证据，表明两种NF-？在GC反应中，B通路参与记忆B细胞与浆细胞的分化。尽管我们对NF-？B，其在GC B细胞分化中的潜在功能是一个尚未探索的新概念。拟议研究的目的是确定两种NF-？B通路及其各自的亚基影响记忆B细胞和浆细胞前体的细胞分化，以了解B细胞癌中这些通路的组成性激活的生物学后果。我们的中心假设是NF-？B信号通过破坏调节GC B细胞向记忆B细胞或浆细胞分化的转录机制，参与B细胞肿瘤的发病机制。为了实现此应用程序的目标，我们将定义单独的NF-？B途径在GC B细胞体内分化的条件小鼠模型。此外，我们将确定由规范和备选NF-？通过对转录靶点的全基因组鉴定，研究了B途径在分化天然GC B细胞和不同发育阶段GC衍生肿瘤中的作用。我们也将开始确定NF-？B在体内参与淋巴瘤的发病。提出这项研究的基本原理是阐明单独的NF-？B途径在胃癌B细胞分化和剖析每个途径对胃癌淋巴瘤形成的贡献将导致新的预后和/或诊断标志物的鉴定。此外，该结果可能为开发创新的抗癌疗法提供基础，这些疗法可以减少与整个NF-？特异性靶向构成性NF-？B信号在i的水平。)单独的NF-？B途径，ii)个体NF-？B亚基，或iii.)特定的转录目标。

DESCRIPTION (provided by applicant): This research proposal aims to elucidate the mechanisms by which constitutive activation of the nuclear factor-?B (NF-?B) transcription factor complex contributes to the oncogenic transformation of mature B lymphocytes. The majority of B-cell cancers originate from antigen-activated mature B cells that have undergone the germinal center (GC) reaction to generate memory B cells and plasma cells, and the development of several lymphoma subtypes has been linked to the oncogenic transformation of the precursors of memory B cells or plasma cells. Notably, these tumors frequently harbor genetic mutations in NF-?B pathway components that result in the constitutive activation of NF-?B signaling, thus identifying NF-?B as a critical player in GC- lymphomagenesis. These observations underscore the need to elucidate the molecular mechanisms by which NF-?B contributes to the transformation of the tumor precursor cells. NF-?B activation can occur via two different routes, the canonical and the alternative pathways, mediated by specific NF-?B subunits. We have obtained preliminary evidence suggesting that differential activation of the two NF-?B pathways is involved in memory B-cell versus plasma cell differentiation during the GC reaction. Despite extensive knowledge about the biology of NF-?B, its potential function in the differentiation of GC B cells is a novel concept that has not been explored. The objective of the proposed research is to determine the mechanisms by which the two NF-?B pathways and their respective subunits affect the cellular differentiation of memory B-cell and plasma cell precursors in order to understand the biological consequences of a constitutive activation of these pathways in B-cell cancers. Our central hypothesis is that constitutive activation of NF-?B signaling contributes to the pathogenesis of B-cell tumors by disrupting the transcriptional mechanisms that regulate the differentiation of a GC B cell into a memory B cell or a plasma cell. To accomplish the objective of this application, we will define the roles of the separate NF-?B pathways in the differentiation of GC B cells in vivo using conditional mouse models. In addition, we will identify the biological programs controlled by the canonical and the alternative NF-?B pathways in differentiating native GC B cells and in GC-derived tumors of various developmental stages by performing a genome-wide identification of the transcriptional targets. We will also start to determine the extent to which NF-?B is involved in lymphoma pathogenesis in vivo. The rationale for the proposed research is that elucidating the role of the separate NF-?B pathways in GC B-cell differentiation and dissecting the contribution of each pathway to GC-lymphomagenesis will lead to the identification of new prognostic and/or diagnostic markers. Moreover, the results may provide the basis for developing innovative anti-cancer therapies that could reduce the adverse systemic side effects associated with the pharmacological inhibition of the entire NF-?B pathway by specifically targeting constitutive NF-?B signaling at the level of i.) the separate NF-?B pathways, ii.) the individual NF-?B subunits, or iii.) the specific transcriptional targets.