RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling

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. und Zimber-Strobl, Ursula (2022): RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling. In: Frontiers in Immunology, Bd. 13, 913275

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-kappa B 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-kappa B 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-kB 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1664-3224
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 278529602
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 278529602