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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

基本信息

批准号：
8998932
负责人：
ULF KLEIN
金额：
$ 33.14万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8998932
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 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&apos 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 diagnostic biomarker 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

项目摘要

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。