RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling
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 activat...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.913275/full |
| _version_ | 1828353066355654656 |
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| author | Laura B. Kuhn Stefanie Valentin Kristina Stojanovic Daniel C. Strobl Tea Babushku Tea Babushku Yan Wang Ursula Rambold Laura Scheffler Sonja Grath Dorothy John-Robbert Helmut Blum Annette Feuchtinger Andreas Blutke Falk Weih Daisuke Kitamura Roland Rad Roland Rad Roland Rad Lothar J. Strobl Ursula Zimber-Strobl |
| author_facet | Laura B. Kuhn Stefanie Valentin Kristina Stojanovic Daniel C. Strobl Tea Babushku Tea Babushku Yan Wang Ursula Rambold Laura Scheffler Sonja Grath Dorothy John-Robbert Helmut Blum Annette Feuchtinger Andreas Blutke Falk Weih Daisuke Kitamura Roland Rad Roland Rad Roland Rad Lothar J. Strobl Ursula Zimber-Strobl |
| author_sort | Laura B. Kuhn |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T02:02:21Z |
| format | Article |
| id | doaj.art-54c53ebf14244ecf932108fe1c3c9659 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T02:02:21Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-54c53ebf14244ecf932108fe1c3c96592022-12-22T02:18:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.913275913275RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signalingLaura B. Kuhn0Stefanie Valentin1Kristina Stojanovic2Daniel C. Strobl3Tea Babushku4Tea Babushku5Yan Wang6Ursula Rambold7Laura Scheffler8Sonja Grath9Dorothy John-Robbert10Helmut Blum11Annette Feuchtinger12Andreas Blutke13Falk Weih14Daisuke Kitamura15Roland Rad16Roland Rad17Roland Rad18Lothar J. Strobl19Ursula Zimber-Strobl20Institute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Molecular Oncology and Functional Genomics, Technical University of Munich (TUM) School of Medicine, Technical University of Munich, Munich, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Asthma and Allergy Prevention, Helmholtz Zentrum München, German Research Center for Environmental Health., Munich, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyDivision of Evolutionary Biology, Faculty of Biology, Ludwig-Maximilians-Universität (LMU), Planegg-Martinsried, GermanyDivision of Evolutionary Biology, Faculty of Biology, Ludwig-Maximilians-Universität (LMU), Planegg-Martinsried, GermanyLaboratory for Functional Genome Analysis, Gene-Center, Ludwig-Maximilians-Universität (LMU), Munich, GermanyResearch Unit Analytical Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, GermanyResearch Unit Analytical Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, GermanyResearch Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, GermanyResearch Institute for Biomedical Sciences, Tokyo University of Science, Noda, JapanInstitute of Molecular Oncology and Functional Genomics, Technical University of Munich (TUM) School of Medicine, Technical University of Munich, Munich, Germany0TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany1Cancer Consortium (DKTK), Heidelberg, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Lung Health and Immunity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyActivation 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.913275/fullCD40non-canonical NF-ĸB-signalingRelBIL9Rtransgenic miceB cell lymphoma |
| spellingShingle | Laura B. Kuhn Stefanie Valentin Kristina Stojanovic Daniel C. Strobl Tea Babushku Tea Babushku Yan Wang Ursula Rambold Laura Scheffler Sonja Grath Dorothy John-Robbert Helmut Blum Annette Feuchtinger Andreas Blutke Falk Weih Daisuke Kitamura Roland Rad Roland Rad Roland Rad Lothar J. Strobl Ursula Zimber-Strobl RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling Frontiers in Immunology CD40 non-canonical NF-ĸB-signaling RelB IL9R transgenic mice B cell lymphoma |
| title | RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling |
| title_full | RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling |
| title_fullStr | RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling |
| title_full_unstemmed | RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling |
| title_short | RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling |
| title_sort | relb contributes to the survival migration and lymphomagenesis of b cells with constitutively active cd40 signaling |
| topic | CD40 non-canonical NF-ĸB-signaling RelB IL9R transgenic mice B cell lymphoma |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.913275/full |
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