CK2β-regulated signaling controls B cell differentiation and function
Serine-Threonine kinase CK2 supports malignant B-lymphocyte growth but its role in B-cell development and activation is largely unknown. Here, we describe the first B-cell specific knockout (KO) mouse model of the β regulatory subunit of CK2. CK2βKO mice present an increase in marginal zone (MZ) and...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.959138/full |
| _version_ | 1828067121148461056 |
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| author | Laura Quotti Tubi Laura Quotti Tubi Elisa Mandato Elisa Mandato Elisa Mandato Sara Canovas Nunes Sara Canovas Nunes Sara Canovas Nunes Arash Arjomand Arash Arjomand Fortunato Zaffino Fortunato Zaffino Sabrina Manni Sabrina Manni Alessandro Casellato Alessandro Casellato Paolo Macaccaro Paolo Macaccaro Nicola Vitulo Sara Zumerle Odile Filhol Brigitte Boldyreff Christian W. Siebel Antonella Viola Giorgio Valle Federica Mainoldi Stefano Casola Valeria Cancila Alessandro Gulino Claudio Tripodo Claudio Tripodo Marco Pizzi Angelo Paolo Dei Tos Livio Trentin Livio Trentin Gianpietro Semenzato Gianpietro Semenzato Francesco Piazza Francesco Piazza |
| author_facet | Laura Quotti Tubi Laura Quotti Tubi Elisa Mandato Elisa Mandato Elisa Mandato Sara Canovas Nunes Sara Canovas Nunes Sara Canovas Nunes Arash Arjomand Arash Arjomand Fortunato Zaffino Fortunato Zaffino Sabrina Manni Sabrina Manni Alessandro Casellato Alessandro Casellato Paolo Macaccaro Paolo Macaccaro Nicola Vitulo Sara Zumerle Odile Filhol Brigitte Boldyreff Christian W. Siebel Antonella Viola Giorgio Valle Federica Mainoldi Stefano Casola Valeria Cancila Alessandro Gulino Claudio Tripodo Claudio Tripodo Marco Pizzi Angelo Paolo Dei Tos Livio Trentin Livio Trentin Gianpietro Semenzato Gianpietro Semenzato Francesco Piazza Francesco Piazza |
| author_sort | Laura Quotti Tubi |
| collection | DOAJ |
| description | Serine-Threonine kinase CK2 supports malignant B-lymphocyte growth but its role in B-cell development and activation is largely unknown. Here, we describe the first B-cell specific knockout (KO) mouse model of the β regulatory subunit of CK2. CK2βKO mice present an increase in marginal zone (MZ) and a reduction in follicular B cells, suggesting a role for CK2 in the regulation of the B cell receptor (BCR) and NOTCH2 signaling pathways. Biochemical analyses demonstrate an increased activation of the NOTCH2 pathway in CK2βKO animals, which sustains MZ B-cell development. Transcriptomic analyses indicate alterations in biological processes involved in immune response and B-cell activation. Upon sheep red blood cells (SRBC) immunization CK2βKO mice exhibit enlarged germinal centers (GCs) but display a limited capacity to generate class-switched GC B cells and immunoglobulins. In vitro assays highlight that B cells lacking CK2β have an impaired signaling downstream of BCR, Toll-like receptor, CD40, and IL-4R all crucial for B-cell activation and antigen presenting efficiency. Somatic hypermutations analysis upon 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Chicken Gamma Globulin (NP-CGG) evidences a reduced NP-specific W33L mutation frequency in CK2βKO mice suggesting the importance of the β subunit in sustaining antibody affinity maturation. Lastly, since diffuse large B cell lymphoma (DLBCL) cells derive from GC or post-GC B cells and rely on CK2 for their survival, we sought to investigate the consequences of CK2 inhibition on B cell signaling in DLBCL cells. In line with the observations in our murine model, CK2 inactivation leads to signaling defects in pathways that are essential for malignant B-lymphocyte activation. |
| first_indexed | 2024-04-10T23:41:18Z |
| format | Article |
| id | doaj.art-42f0f970a71d4dd7a8b8d6085144b412 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T23:41:18Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-42f0f970a71d4dd7a8b8d6085144b4122023-01-11T06:57:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011310.3389/fimmu.2022.959138959138CK2β-regulated signaling controls B cell differentiation and functionLaura Quotti Tubi0Laura Quotti Tubi1Elisa Mandato2Elisa Mandato3Elisa Mandato4Sara Canovas Nunes5Sara Canovas Nunes6Sara Canovas Nunes7Arash Arjomand8Arash Arjomand9Fortunato Zaffino10Fortunato Zaffino11Sabrina Manni12Sabrina Manni13Alessandro Casellato14Alessandro Casellato15Paolo Macaccaro16Paolo Macaccaro17Nicola Vitulo18Sara Zumerle19Odile Filhol20Brigitte Boldyreff21Christian W. Siebel22Antonella Viola23Giorgio Valle24Federica Mainoldi25Stefano Casola26Valeria Cancila27Alessandro Gulino28Claudio Tripodo29Claudio Tripodo30Marco Pizzi31Angelo Paolo Dei Tos32Livio Trentin33Livio Trentin34Gianpietro Semenzato35Gianpietro Semenzato36Francesco Piazza37Francesco Piazza38Department of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United StatesDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Biology, Interdepartmental Research Center for Biotechnologies (CRIBI) Biotechnology Center, University of Padova, Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Padova, ItalyInstitut National de la Santé Et de la Recherche Médicale (INSERM) U1036, Institute de Recherches en Technologies et Sciences pour le Vivant/Biologie du Cancer et de l’Infection, Grenoble, FranceKinase Detect ApS, Krusaa, DenmarkDepartment of Discovery Oncology, Genentech, Inc., South San Francisco, CA, United StatesDepartment of Biomedical Sciences, University of Padova, Padova, ItalyDepartment of Biology, Interdepartmental Research Center for Biotechnologies (CRIBI) Biotechnology Center, University of Padova, Padova, Italy0IFOM-ETS-The AIRC Institute of Molecular Oncology, Milan, Italy0IFOM-ETS-The AIRC Institute of Molecular Oncology, Milan, Italy1Tumor Immunology Unit, University of Palermo, Palermo, Italy1Tumor Immunology Unit, University of Palermo, Palermo, Italy0IFOM-ETS-The AIRC Institute of Molecular Oncology, Milan, Italy1Tumor Immunology Unit, University of Palermo, Palermo, Italy2Department of Medicine, Cytopathology and Surgical Pathology Unit, University of Padova, Padova, Italy2Department of Medicine, Cytopathology and Surgical Pathology Unit, University of Padova, Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalyDepartment of Medicine, Division of Hematology, University of Padova, Padova, ItalyUnit of Normal and Malignant Hematopoiesis, Laboratory of Myeloma and Lymphoma Pathobiology, Veneto of Molecular Medicine (VIMM), Padova, ItalySerine-Threonine kinase CK2 supports malignant B-lymphocyte growth but its role in B-cell development and activation is largely unknown. Here, we describe the first B-cell specific knockout (KO) mouse model of the β regulatory subunit of CK2. CK2βKO mice present an increase in marginal zone (MZ) and a reduction in follicular B cells, suggesting a role for CK2 in the regulation of the B cell receptor (BCR) and NOTCH2 signaling pathways. Biochemical analyses demonstrate an increased activation of the NOTCH2 pathway in CK2βKO animals, which sustains MZ B-cell development. Transcriptomic analyses indicate alterations in biological processes involved in immune response and B-cell activation. Upon sheep red blood cells (SRBC) immunization CK2βKO mice exhibit enlarged germinal centers (GCs) but display a limited capacity to generate class-switched GC B cells and immunoglobulins. In vitro assays highlight that B cells lacking CK2β have an impaired signaling downstream of BCR, Toll-like receptor, CD40, and IL-4R all crucial for B-cell activation and antigen presenting efficiency. Somatic hypermutations analysis upon 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Chicken Gamma Globulin (NP-CGG) evidences a reduced NP-specific W33L mutation frequency in CK2βKO mice suggesting the importance of the β subunit in sustaining antibody affinity maturation. Lastly, since diffuse large B cell lymphoma (DLBCL) cells derive from GC or post-GC B cells and rely on CK2 for their survival, we sought to investigate the consequences of CK2 inhibition on B cell signaling in DLBCL cells. In line with the observations in our murine model, CK2 inactivation leads to signaling defects in pathways that are essential for malignant B-lymphocyte activation.https://www.frontiersin.org/articles/10.3389/fimmu.2022.959138/fullB lymphocyteB cell developmentprotein kinase CK2marginal zonegerminal centerDiffuse large B cell lymphoma |
| spellingShingle | Laura Quotti Tubi Laura Quotti Tubi Elisa Mandato Elisa Mandato Elisa Mandato Sara Canovas Nunes Sara Canovas Nunes Sara Canovas Nunes Arash Arjomand Arash Arjomand Fortunato Zaffino Fortunato Zaffino Sabrina Manni Sabrina Manni Alessandro Casellato Alessandro Casellato Paolo Macaccaro Paolo Macaccaro Nicola Vitulo Sara Zumerle Odile Filhol Brigitte Boldyreff Christian W. Siebel Antonella Viola Giorgio Valle Federica Mainoldi Stefano Casola Valeria Cancila Alessandro Gulino Claudio Tripodo Claudio Tripodo Marco Pizzi Angelo Paolo Dei Tos Livio Trentin Livio Trentin Gianpietro Semenzato Gianpietro Semenzato Francesco Piazza Francesco Piazza CK2β-regulated signaling controls B cell differentiation and function Frontiers in Immunology B lymphocyte B cell development protein kinase CK2 marginal zone germinal center Diffuse large B cell lymphoma |
| title | CK2β-regulated signaling controls B cell differentiation and function |
| title_full | CK2β-regulated signaling controls B cell differentiation and function |
| title_fullStr | CK2β-regulated signaling controls B cell differentiation and function |
| title_full_unstemmed | CK2β-regulated signaling controls B cell differentiation and function |
| title_short | CK2β-regulated signaling controls B cell differentiation and function |
| title_sort | ck2β regulated signaling controls b cell differentiation and function |
| topic | B lymphocyte B cell development protein kinase CK2 marginal zone germinal center Diffuse large B cell lymphoma |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.959138/full |
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