title: Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation.
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.
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Romero-Camarero
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lu
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.forename: Ines
authors.initials: I
authors.lastname: Gonzalez-Herrero
authors.forename: Teresa
authors.initials: T
authors.lastname: Flores
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Garcia
authors.forename: George
authors.initials: G
authors.lastname: McNamara
authors.forename: Christian
authors.initials: C
authors.lastname: Kunder
authors.forename: Shuchun
authors.initials: S
authors.lastname: Zhao
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.forename: Lorena
authors.initials: L
authors.lastname: Fontan
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martínez-Climent
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: García-Criado
authors.forename: Jason D
authors.initials: JD
authors.lastname: Theis
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: Elena
authors.initials: E
authors.lastname: Campos-Sánchez
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Cesar
authors.initials: C
authors.lastname: Cobaleda
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000150:complications / Q000473:pathology*; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002457:Cell Extracts; D004195:Disease Models, Animal; D004789:Enzyme Activation; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006942:Hypergammaglobulinemia / Q000473:pathology; D006965:Hyperplasia; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D000072377:Syk Kinase; D059467:Transcriptome / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D002457:Cell Extracts; C476824:GCSAM protein, human; D047908:Intracellular Signaling Peptides and Proteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D020742:rhoA GTP-Binding Protein