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

NF-kB 在 B 细胞分化和淋巴瘤发生中的作用

• 批准号: 8823740
• 负责人: ULF KLEIN
• 金额: $ 33.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823740
• 关键词: Address; Adverse effects; Affect; Algorithms; Animal Model; Antigens; B cell differentiation; B lymphoid malignancy; B-Cell Neoplasm; B-Lymphocytes; Binding; Biological; Biological Assay; Biology; Cancer Etiology; Cell Survival; Chronic Lymphocytic Leukemia; Complement Factor B; Complex; DNA Sequence Alteration; Development; Diagnostic; Effector Cell; Engineering; Gene Expression Profiling; Genes; Hodgkin Disease; Immune response; Immunity; Individual; Innovative Therapy; Knowledge; Lead; Link; Lymphoid; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Medicine; Memory B-Lymphocyte; Mission; Molecular; Multiple Myeloma; NF-kappa B; Non-Hodgkin' s Lymphoma; Normal Cell; Nuclear; Oncogenic; Pathogenesis; Pathway interactions; Plasma Cells; Process; Public Health; RELA gene; Reaction; Research; Research Proposals; Role; Route; Signal Pathway; Signal Transduction; Small-Cell Lymphoma; Staging; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Tumor-Derived; United States National Institutes of Health; Work; base; cancer therapy; cell growth; effective therapy; genome-wide; genome-wide analysis; in vivo; innovation; knockout animal; mouse model; novel; outcome forecast; plasma cell development; plasma cell differentiation; precursor cell; prognostic; programs; promoter; reconstruction; transcription factor; tumor; tumorigenesis

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.

描述（由申请方提供）：本研究计划旨在阐明核因子-κB（NF-κB）转录因子复合物的组成性激活促进成熟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-κB途径组分中具有导致NF-κB信号传导的组成性活化的基因突变，因此鉴定NF-κB为GC-淋巴瘤发生中的关键参与者。这些观察结果强调需要阐明NF-κB参与肿瘤前体细胞转化的分子机制。NF-κB的活化可以通过两种不同的途径发生，即经典途径和替代途径，由特定的NF-κB亚基介导。我们获得的初步证据表明，两个NF-κB通路的差异激活参与了GC反应过程中记忆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。本研究的目的是确定两种NF-κB通路及其各自亚基影响记忆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细胞癌中组成性激活的生物学后果。我们的中心假设是NF-κB信号的组成性激活通过破坏调节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。为了实现本申请的目的，我们将使用条件性小鼠模型来确定单独的NF-κB途径在体内GC B细胞分化中的作用。此外，我们将通过对转录靶点进行全基因组鉴定，确定在分化天然GC B细胞和不同发育阶段的GC衍生肿瘤中由经典和替代NF-κB途径控制的生物学程序。我们还将开始确定NF-κB在体内淋巴瘤发病机制中的参与程度。提出的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，并剖析每个通路对GC淋巴瘤发生的贡献，将导致新的预后和/或诊断标志物的鉴定。此外，该结果可以为开发创新的抗癌疗法提供基础，该疗法可以通过在i.）水平特异性靶向组成型NF-κ B信号传导来减少与整个NF-κB通路的药理学抑制相关的不良全身副作用。单独的NF-κB通路，ii.）单个NF-κB亚基，或iii.）特定的转录靶点。