A20 deficiency and deregulated Notch2 signaling in lymphomagenesis and autoimmunity

A20 缺陷和淋巴瘤发生和自身免疫中 Notch2 信号失调

• 批准号: 273068069
• 负责人: Professor Dr. Marc Schmidt-Supprian
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III: Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/273068069?language=en
• 关键词: A20; deficiency; deregulated; Notch2; signaling

The immune system protects us from pathogens but deregulated immune signals can cause severe immunopathologies, such as cancer and autoimmunity. Many genes that encode components of signaling pathways regulating the differentiation, proliferation and apoptosis of immune cells are mutated in these diseases. Our application is focused on the investigation of deregulated NF-kB and Notch2 signaling in B cell differentiation and immune diseases. Both signaling pathways regulate the differentiation of Marginal Zone (MZ) B cells and are frequently hyperactivated in lymphomas, the most common cancer of immune cells. NF-kB transcription factors regulate genes involved in inflammation, proliferation and survival. Polymorphisms in and near the TNFAIP3/A20 gene locus, which encodes the A20 negative feedback inhibitor of NF-kB activation, are linked to human autoimmune diseases. Importantly, of all genomic aberrations causing elevated NF-kB activity in human lymphomas, functional loss of A20 is the most common, underscoring the critical role of A20 in human disease. Recently, we showed that ablation of A20 specifically in B cells impairs their differentiation and causes an autoimmune syndrome in aged mice. Notch 1-4 are members of a transmembrane receptor family that is involved in manifold cell fate decisions. We showed that B cell specific expression of constitutively active Notch 2 (Notch2IC) drives nearly all B cells into the MZ B cell compartment. Mutations in the NOTCH2 gene resulting in increased stability of NOTCH2 have been recurrently found in human splenic MZ B cell lymphoma (SMZL) and Diffuse Large B cell lymphomas (DLBCL). Our current data indicate that Notch2IC is not acting as a strong oncogene in B cells. The reason might be that Notch2IC induces proliferation as well as apoptosis in mature B cells. Fittingly, simultaneously with Notch2 recurrent mutations in genes leading to the activation of canonical and non-canonical NF-kB signaling have been detected in human SMZL. Therefore, we postulate that deregulated Notch2 signaling causes B cell lymphomas only in combination with antiapoptotic signals, such as NF-kB activation. The goals of our application are to study pathogenic functions of A20 deficiency and enhanced Notch2 signaling alone and in combination in B-cell mediated diseases: (i) We aim to characterize how signaling pathways downstream of IL17R and TLRs cause immunopathology in A20-deficient B cells. Furthermore, we propose to test the hypothesis that enhanced levels of BAFF synergize with loss of A20 in autoimmunity. (ii) By studying the consequences of deregulated Notch2 signaling in activated MZ B and germinal center B cells, we aim to explore the influence of deregulated Notch signaling in activated B lymphocytes. (iii) Our common goal is to investigate the cooperation between enhanced Notch2 signaling and deregulated NF-kB (A20-deficiency, LMP1/CD40 expression) signaling in B cell lymphoma development and autoimmunity.

免疫系统保护我们免受病原体的侵袭，但免疫信号失控会导致严重的免疫病理，如癌症和自身免疫。在这些疾病中，许多编码调节免疫细胞分化、增殖和凋亡的信号通路组件的基因发生了突变。我们的应用主要集中在研究去调控的核因子-kB和Notch2信号在B细胞分化和免疫疾病中的作用。这两个信号通路调节边缘带(MZ)B细胞的分化，在淋巴瘤中经常过度激活，淋巴瘤是最常见的免疫细胞癌。核因子-kB转录因子调控与炎症、增殖和生存相关的基因。编码核因子-kB激活的负反馈抑制因子A20的TNFAIP3/A20基因位点及其附近的多态与人类自身免疫性疾病有关。重要的是，在所有导致人类淋巴瘤核因子-kB活性升高的基因组异常中，A20的功能丧失是最常见的，这突显了A20在人类疾病中的关键作用。最近，我们发现去除B细胞中的A20会损害B细胞的分化，并导致老年小鼠的自身免疫综合征。缺口1-4是跨膜受体家族的成员，参与多种细胞命运的决定。我们发现B细胞特异性表达的组成性活性Notch 2(Notch2IC)可以驱使几乎所有的B细胞进入MZ B细胞室。NOTCH2基因突变导致NOTCH2的稳定性增加，目前在人脾MZ B细胞淋巴瘤(SMZL)和弥漫性大B细胞淋巴瘤(DLBCL)中反复发现。我们目前的数据表明，Notch2IC在B细胞中并不是一个很强的癌基因。其原因可能与Notch2IC诱导成熟B细胞增殖和凋亡有关。与Notch2同步，在人类SMZL中也检测到导致典型和非典型核因子-kB信号激活的基因的反复突变。因此，我们推测，解除调控的Notch2信号只会与抗凋亡信号(如NF-kB激活)结合在一起导致B细胞淋巴瘤。我们应用的目的是研究A20缺乏和Notch2信号增强在B细胞介导的疾病中的致病功能：(I)我们的目标是表征IL17R和TLRs下游的信号通路如何导致A20缺乏的B细胞的免疫病理。此外，我们建议检验在自身免疫中BAFF水平的增加与A20的丢失具有协同作用的假设。(Ii)通过研究Notch2信号在激活的MZ B细胞和生发中心B细胞中的后果，我们的目的是探索Notch信号在激活的B淋巴细胞中的影响。(3)我们的共同目标是研究增强的Notch2信号和非调控的NF-kB(A20缺失，LMP1/CD40表达)信号在B细胞淋巴瘤发生和自身免疫中的协同作用。