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

描述(申请人提供)：这项研究计划旨在阐明核因子-κB(核因子-κB)转录因子复合体的结构性激活促进成熟B淋巴细胞致癌转化的机制。大多数B细胞癌起源于抗原激活的成熟B细胞，它们经过生发中心(GC)反应产生记忆B细胞和浆细胞，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，这些肿瘤经常在NF-κB通路成分中存在基因突变，导致NF-κB信号的结构性激活，从而确定NF-κB在GC-淋巴瘤发生中起关键作用。这些观察结果强调了阐明NF-κB促进肿瘤前体细胞转化的分子机制的必要性。核因子-κB的激活可以通过两种不同的途径发生，即由特定的核因子-κB亚基介导的规范途径和替代途径。我们已经获得的初步证据表明，在GC反应中，两条NF-κB通路的差异激活参与了记忆B细胞与浆细胞的分化。尽管对NF-κB的生物学有广泛的了解，但它在GC B细胞分化中的潜在功能是一个新的概念，还没有被探索过。本研究的目的是确定两条NF-κB通路及其各自的亚单位影响记忆B细胞和浆细胞前体细胞分化的机制，以了解这些通路的结构性激活在B细胞癌中的生物学后果。我们的中心假设是，NF-κB信号的结构性激活通过破坏调控GC B细胞向记忆B细胞或浆细胞分化的转录机制而参与B细胞肿瘤的发病。为了实现这一应用的目标，我们将使用条件性小鼠模型来确定单独的NF-κB通路在体内GC B细胞分化中的作用。此外，我们将通过对转录靶标的全基因组鉴定，确定在分化天然GC B细胞和不同发育阶段的GC来源的肿瘤时，由规范的和替代的NF-κB途径控制的生物学程序。我们还将开始确定NF-κB在体内参与淋巴瘤发病的程度。这项研究的基本原理是，阐明单独的NF-κB通路在GC B细胞分化中的作用，并剖析每条通路对GC淋巴肿大的贡献，将导致识别新的预后和/或诊断标记物。此外，这些结果可能为开发创新的抗癌疗法提供基础，这些疗法可以通过在I水平上特异性地针对结构性的NF-κB信号来减少与药物抑制整个NF-κB途径相关的不良全身副作用。)不同的NF-κB通路，II.)单个核因子-κB亚基，或ii.)特定的转录靶点。

DESCRIPTION (provided by applicant): This research proposal aims to elucidate the mechanisms by which constitutive activation of the nuclear factor-κB (NF-κB) 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-κB pathway components that result in the constitutive activation of NF-κB signaling, thus identifying NF-κB as a critical player in GC- lymphomagenesis. These observations underscore the need to elucidate the molecular mechanisms by which NF-κB contributes to the transformation of the tumor precursor cells. NF-κB activation can occur via two different routes, the canonical and the alternative pathways, mediated by specific NF-κB subunits. We have obtained preliminary evidence suggesting that differential activation of the two NF-κB pathways is involved in memory B-cell versus plasma cell differentiation during the GC reaction. Despite extensive knowledge about the biology of NF-κB, 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-κB 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-κB 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-κB 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-κB 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-κB is involved in lymphoma pathogenesis in vivo. The rationale for the proposed research is that elucidating the role of the separate NF-κB 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-κB pathway by specifically targeting constitutive NF-κB signaling at the level of i.) the separate NF-κB pathways, ii.) the individual NF-κB subunits, or iii.) the specific transcriptional targets.