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-B(核因子-B)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，这些肿瘤经常在核因子-βB途径成分中存在基因突变，导致核因子-βB信号的结构性激活，从而确认核因子-βB在GC-淋巴肿大中起关键作用。这些观察结果强调了阐明核因子-βB促进肿瘤前体细胞转化的分子机制的必要性。核因子-βB的激活可以通过两种不同的途径发生，即由特定的核因子-β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，这两条核因子-βB通路的差异激活参与了记忆B细胞与浆细胞的分化。尽管对核因子-B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。本研究的目的是确定两条核因子-βB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，以了解这些通路在B细胞癌中的组成性激活的生物学后果。我们的中心假设是，NF-B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不同的NF-B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进行全基因组鉴定，确定在分化天然GC B细胞和不同发育阶段的GC来源的肿瘤过程中，由规范的和替代的NF-？B途径控制的生物学程序。我们还将开始确定核因子-βB在体内淋巴瘤发病机制中的参与程度。这项研究的基本原理是，阐明单独的NF-B通路在GC-B细胞分化中的作用，并剖析每条通路在GC-淋巴瘤发生中的作用，将有助于识别新的预后和/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.不同的NF-B通路，II.)单个核因子-βB亚基，或III。)特定的转录靶点。 公共卫生相关性：拟议的研究与公共健康相关，因为霍奇金淋巴瘤和非霍奇金淋巴瘤以及多发性骨髓瘤，其中大多数显示出结构性的核因子-β激活，往往预后不良，他们的治疗对医学来说是一个重大挑战。这项研究的基本原理是，一旦核因子-βB在B细胞恶性肿瘤发病机制中的生物学作用被了解，就有了开发针对淋巴癌的旨在抑制核因子-βB的创新疗法的基础。因此，拟议的研究与美国国立卫生研究院关于了解癌症原因和随后开发有效治疗方法的使命相关。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because Hodgkin and Non-Hodgkin lymphomas as well as multiple myeloma, the majority of which shows constitutive NF-?B activation, often have an unfavorable prognosis and their treatment represents a major challenge for medicine. The rationale for the proposed research is that once the biology of NF-?B in the pathogenesis of B-cell malignancies is known, there will be a basis for developing innovative therapies against lymphoid cancer that are aimed at inhibiting NF-?B. Thus, the proposed research is relevant to the mission of the NIH pertaining to the understanding of the causes of cancer and the subsequent development of effective treatments.