Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation

Isabel Romero-Camarero, Xiaoyu Jiang, Yasodha Natkunam, Xiaoqing Lu, Carolina Vicente-Dueñas, Ines Gonzalez-Herrero, Teresa Flores, Juan Luis Garcia, George McNamara, Christian Kunder, Shuchun Zhao, Victor Segura, Lorena Fontan, Jose A. Martínez-Climent, Francisco Javier García-Criado, Jason D. Theis, Ahmet Dogan, Elena Campos-Sánchez, Michael R. Green, Ash A. Alizadeh, Cesar Cobaleda, Isidro Sánchez-García () and Izidore S Lossos ()
Additional contact information
Isabel Romero-Camarero: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca
Xiaoyu Jiang: University of Miami, Sylvester Comprehensive Cancer Center
Yasodha Natkunam: Stanford University School of Medicine
Xiaoqing Lu: University of Miami, Sylvester Comprehensive Cancer Center
Carolina Vicente-Dueñas: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca
Ines Gonzalez-Herrero: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca
Teresa Flores: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca
Juan Luis Garcia: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca
George McNamara: Analytical Imaging Core Facility (AICF), University of Miami
Christian Kunder: Stanford University School of Medicine
Shuchun Zhao: Stanford University School of Medicine
Victor Segura: Center for Applied Medical Research (CIMA), University of Navarra
Lorena Fontan: Center for Applied Medical Research (CIMA), University of Navarra
Jose A. Martínez-Climent: Center for Applied Medical Research (CIMA), University of Navarra
Francisco Javier García-Criado: University of Salamanca
Jason D. Theis: Mayo Clinic
Ahmet Dogan: Mayo Clinic
Elena Campos-Sánchez: Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma
Michael R. Green: Stanford University School of Medicine
Ash A. Alizadeh: Stanford University School of Medicine
Cesar Cobaleda: Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma
Isidro Sánchez-García: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca
Izidore S Lossos: University of Miami, Sylvester Comprehensive Cancer Center

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation.

Date: 2013
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DOI: 10.1038/ncomms2334

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