Institute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Front Immunol. 2022 Aug 30;13:913275. doi: 10.3389/fimmu.2022.913275. eCollection 2022.
Activation of CD40-signaling contributes to the initiation, progression and drug resistance of B cell lymphomas. We contributed to this knowledge by showing that constitutive CD40-signaling in B cells induces B cell hyperplasia and finally B cell lymphoma development in transgenic mice. CD40 activates, among others, the non-canonical NF-ĸB signaling, which is constitutively activated in several human B cell lymphomas and is therefore presumed to contribute to lymphopathogenesis. This prompted us to study the regulatory role of the non-canonical NF-ĸB transcription factor RelB in lymphomagenesis. To this end, we crossed mice expressing a constitutively active CD40 receptor in B cells with conditional RelB-KO mice. Ablation of RelB attenuated pre-malignant B cell expansion, and resulted in an impaired survival and activation of long-term CD40-stimulated B cells. Furthermore, we found that hyperactivation of non-canonical NF-кB signaling enhances the retention of B cells in the follicles of secondary lymphoid organs. RNA-Seq-analysis revealed that several genes involved in B-cell migration, survival, proliferation and cytokine signaling govern the transcriptional differences modulated by the ablation of RelB in long-term CD40-stimulated B cells. Inactivation of RelB did not abrogate lymphoma development. However, lymphomas occurred with a lower incidence and had a longer latency period. In summary, our data suggest that RelB, although it is not strictly required for malignant transformation, accelerates the lymphomagenesis of long-term CD40-stimulated B cells by regulating genes involved in migration, survival and cytokine signaling.
CD40 信号的激活有助于 B 细胞淋巴瘤的起始、进展和耐药。我们通过显示 B 细胞中组成性的 CD40 信号会诱导 B 细胞增生，最终导致转基因小鼠发生 B 细胞淋巴瘤发展，为这一知识做出了贡献。CD40 激活了非经典 NF-κB 信号通路，该信号通路在几种人类 B 细胞淋巴瘤中持续激活，因此被认为有助于淋巴瘤发病机制。这促使我们研究非经典 NF-κB 转录因子 RelB 在淋巴瘤发生中的调节作用。为此，我们将在 B 细胞中表达组成性激活的 CD40 受体的小鼠与条件性 RelB-KO 小鼠进行杂交。RelB 的缺失减弱了前恶性 B 细胞的扩增，并导致长期 CD40 刺激的 B 细胞的存活和激活受损。此外，我们发现非经典 NF-κB 信号通路的过度激活增强了次级淋巴器官滤泡中 B 细胞的保留。RNA-Seq 分析表明，几个参与 B 细胞迁移、存活、增殖和细胞因子信号的基因调控了 RelB 缺失在长期 CD40 刺激的 B 细胞中转录差异。RelB 的失活并没有阻止淋巴瘤的发展。然而，淋巴瘤的发生率较低，潜伏期较长。总之，我们的数据表明，虽然 RelB 对于恶性转化不是严格必需的，但通过调节参与迁移、存活和细胞因子信号的基因，加速了长期 CD40 刺激的 B 细胞的淋巴瘤发生。
