RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling.
RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling.
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DOI：
10.3389/fimmu.2022.913275
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发表时间：
2022
影响因子：
7.3
通讯作者：
Zimber-Strobl, Ursula
中科院分区：
文献类型：
--
作者：
Kuhn, Laura B.;Valentin, Stefanie;Stojanovic, Kristina;Strobl, Daniel C.;Babushku, Tea;Wang, Yan;Rambold, Ursula;Scheffler, Laura;Grath, Sonja;John-Robbert, Dorothy;Blum, Helmut;Feuchtinger, Annette;Blutke, Andreas;Weih, Falk;Kitamura, Daisuke;Rad, Roland;Strobl, Lothar J.;Zimber-Strobl, Ursula
CD 40信号的激活有助于B细胞淋巴瘤的发生、发展和耐药性。我们通过证明B细胞中的组成性CD 40信号传导诱导转基因小鼠中的B细胞增生并最终诱导B细胞淋巴瘤的发展，为这一认识做出了贡献。CD 40尤其激活非经典NF-κ B B信号传导，其在几种人B细胞淋巴瘤中被组成性激活，因此推测其有助于淋巴病发生。这促使我们研究非经典NF-κ B转录因子RelB在淋巴瘤发生中的调节作用。为此，我们将在B细胞中表达组成型活性CD 40受体的小鼠与条件性RelB-KO小鼠杂交。RelB的消融减弱了癌前B细胞扩增，并导致长期CD 40刺激的B细胞的存活和活化受损。此外，我们发现非经典NF-B信号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-分析显示，参与B细胞迁移、存活、增殖和细胞因子信号传导的几个基因控制了在长期CD 40刺激的B细胞中通过消除RelB调节的转录差异。RelB的失活并没有消除淋巴瘤的发展。而淋巴瘤的发病率较低，潜伏期较长。总之，我们的数据表明，RelB，虽然它不是严格要求恶性转化，加速淋巴瘤的长期CD 40刺激的B细胞通过调节基因参与迁移，生存和细胞因子信号。
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.
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影响因子：
5.4
作者：
DApuzzo, M;Rolink, A;Moser, B
通讯作者：
Moser, B
DOI：
10.1084/jem.194.1.45
发表时间：
2001-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hargreaves DC;Hyman PL;Lu TT;Ngo VN;Bidgol A;Suzuki G;Zou YR;Littman DR;Cyster JG
通讯作者：
Cyster JG
DOI：
10.1073/pnas.1602728113
发表时间：
2016-08-09
影响因子：
11.1
作者：
De Silva, Nilushi S.;Anderson, Michael M.;Klein, Ulf
通讯作者：
Klein, Ulf
DOI：
10.4049/jimmunol.1501120
发表时间：
2016-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
De Silva NS;Silva K;Anderson MM;Bhagat G;Klein U
通讯作者：
Klein U
影响因子：
30.5
作者：
Claudio, E;Brown, K;Siebenlist, U
通讯作者：
Siebenlist, U