1. RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling.
- Author
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Kuhn LB, Valentin S, Stojanovic K, Strobl DC, Babushku T, Wang Y, Rambold U, Scheffler L, Grath S, John-Robbert D, Blum H, Feuchtinger A, Blutke A, Weih F, Kitamura D, Rad R, Strobl LJ, and Zimber-Strobl U
- Subjects
- Animals, B-Lymphocytes, CD40 Antigens genetics, Cytokines, Humans, Mice, Mice, Transgenic, NF-kappa B, Lymphoma, Lymphoma, B-Cell genetics, Transcription Factor RelB genetics
- Abstract
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kuhn, Valentin, Stojanovic, Strobl, Babushku, Wang, Rambold, Scheffler, Grath, John-Robbert, Blum, Feuchtinger, Blutke, Weih, Kitamura, Rad, Strobl and Zimber-Strobl.)
- Published
- 2022
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