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Kuhn, L. ; Valentin, S. ; Stojanovic, K. ; Strobl, D.C. ; 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, L.J. ; Zimber-Strobl, U.

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

Front. Immunol. 13:913275 (2022)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cd40 ; Non-canonical Nf-kappa B-signaling ; Relb ; Il9r ; Transgenic Mice ; B Cell Lymphoma ; Migration ; Lilrb4

ISSN (print) / ISBN 1664-3224

e-ISSN 1664-3224

Journal Frontiers in Immunology

Quellenangaben Volume: 13, Article Number: 913275

Publisher Frontiers

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Gene Vector (AGV)
Institute of Computational Biology (ICB)
Institute of Asthma and Allergy Prevention (IAP)
CF Pathology & Tissue Analytics (CF-PTA)
Institute of Lung Health and Immunity (LHI)

Grants Deutsche Krebshilfe
Deutsche Forschungsgemeinschaft