TY - JOUR
T1 - Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
AU - Romero-Camarero, Isabel
AU - Jiang, Xiaoyu
AU - Natkunam, Yasodha
AU - Lu, Xiaoqing
AU - Vicente-Dueñas, Carolina
AU - Gonzalez-Herrero, Ines
AU - Flores, Teresa
AU - Garcia, Juan Luis
AU - McNamara, George
AU - Kunder, Christian
AU - Zhao, Shuchun
AU - Segura, Victor
AU - Fontan, Lorena
AU - Martínez-Climent, Jose A.
AU - García-Criado, Francisco Javier
AU - Theis, Jason D.
AU - Dogan, Ahmet
AU - Campos-Sánchez, Elena
AU - Green, Michael R.
AU - Alizadeh, Ash A.
AU - Cobaleda, Cesar
AU - Sánchez-García, Isidro
AU - Lossos, Izidore S.
N1 - Funding Information:
Grant support: I.S.L. is supported by National Institutes of Health (NIH) grants NIH CA109335 and NIH CA122105, and the Dwoskin Family Foundations. Y.N. is supported by NIH P01 CA34233. Research in ISG group was partially supported by FEDER and by MICINN (SAF2009-08803 and SAF2012-32810 to ISG), by Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010), by MEC OncoBIO Con-solider-Ingenio 2010 (Ref. CSD2007-0017), by Sandra Ibarra Foundation, by Group of Excellence Grant (GR15) from Junta de Castilla y Leon and the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Programme), and by Proyecto en Red de Investigación en Celulas Madre Tumorales en Cancer de Mama, supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms2334
DO - 10.1038/ncomms2334
M3 - Article
C2 - 23299888
AN - SCOPUS:84878539934
SN - 2041-1723
VL - 4
JO - Nature Communications
JF - Nature Communications
M1 - 1338
ER -