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，其经历了生发中心（GC）反应以产生记忆B细胞和浆细胞，并且几种淋巴瘤亚型的发展与记忆B细胞或浆细胞的前体的致癌转化有关。值得注意的是，这些肿瘤经常在NF-？B途径的组成部分，导致NF-？B信号，从而确定NF-？B作为GC-淋巴瘤发生的关键参与者。这些意见强调需要阐明的分子机制，NF-？B有助于肿瘤前体细胞的转化。NF-？B激活可以通过两种不同的途径发生，典型的和替代途径，由特定的NF-？B亚单位。我们已经获得的初步证据表明，差异激活的两个NF-？B途径参与GC反应期间记忆B细胞与浆细胞的分化。尽管对NF-？B，其在GC B细胞分化中的潜在功能是尚未探索的新概念。拟议的研究的目的是确定的机制，这两个NF-？B途径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，以了解这些途径在B细胞癌症中的组成性激活的生物学后果。我们的中心假设是，组成性激活NF-？B信号传导通过破坏调节GC B细胞分化为记忆B细胞或浆细胞的转录机制而促成B细胞肿瘤的发病。为了实现这个应用程序的目标，我们将定义单独的NF-？使用条件小鼠模型在体内GC B细胞分化中的B途径。此外，我们将确定生物程序控制的典型和替代NF-？B途径在分化天然GC B细胞和不同发育阶段的GC衍生肿瘤中的作用。我们还将开始确定NF-？B参与体内淋巴瘤的发病机制。提出的研究的理由是，阐明单独的NF-？B途径在GC B细胞分化和解剖的GC-淋巴瘤发生的每一个途径的贡献将导致新的预后和/或诊断标志物的鉴定。此外，这些结果可能为开发创新的抗癌疗法提供基础，这些疗法可以减少与整个NF-κ B的药理学抑制相关的不良全身副作用。B途径特异性靶向组成型NF-？在i.）水平上的B信令。单独的NF-？B途径，ii.）个人NF-？B亚基，或iii.）特定的转录靶点。 公共卫生相关性：拟议的研究是相关的公共卫生，因为霍奇金淋巴瘤和非霍奇金淋巴瘤以及多发性骨髓瘤，其中大部分显示组成性NF-？B活化通常具有不利的预后，并且它们的治疗代表了医学的主要挑战。拟议研究的理由是，一旦NF-？B在B细胞恶性肿瘤的发病机制是已知的，将有一个基础，为发展创新的治疗方法，对淋巴癌的目的是抑制NF-？B。因此，拟议的研究与NIH的使命有关，即了解癌症的病因和随后开发有效的治疗方法。

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.