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; Izidore S. Lossos

doi:10.1038/ncomms2334

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. AlizadehCesar Cobaleda, Isidro Sánchez-García, Izidore S. Lossos

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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.

Original language	English (US)
Article number	1338
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2334
State	Published - 2013

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Romero-Camarero, I., Jiang, X., Natkunam, Y., Lu, X., Vicente-Dueñas, C., Gonzalez-Herrero, I., Flores, T., Garcia, J. L., McNamara, G., Kunder, C., Zhao, S., Segura, V., Fontan, L., Martínez-Climent, J. A., García-Criado, F. J., Theis, J. D., Dogan, A., Campos-Sánchez, E., Green, M. R., ... Lossos, I. S. (2013). Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation. Nature communications, 4, Article 1338. https://doi.org/10.1038/ncomms2334

Romero-Camarero, I, Jiang, X, Natkunam, Y, Lu, X, Vicente-Dueñas, C, Gonzalez-Herrero, I, Flores, T, Garcia, JL, McNamara, G, Kunder, C, Zhao, S, Segura, V, Fontan, L, Martínez-Climent, JA, García-Criado, FJ, Theis, JD, Dogan, A, Campos-Sánchez, E, Green, MR, Alizadeh, AA, Cobaleda, C, Sánchez-García, I & Lossos, IS 2013, 'Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation', Nature communications, vol. 4, 1338. https://doi.org/10.1038/ncomms2334

@article{054588ddab464f86b4083741709642d8,

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.",

author = "Isabel Romero-Camarero and Xiaoyu Jiang and Yasodha Natkunam and Xiaoqing Lu and Carolina Vicente-Due{\~n}as and Ines Gonzalez-Herrero and Teresa Flores and Garcia, {Juan Luis} and George McNamara and Christian Kunder and Shuchun Zhao and Victor Segura and Lorena Fontan and Mart{\'i}nez-Climent, {Jose A.} and Garc{\'i}a-Criado, {Francisco Javier} and Theis, {Jason D.} and Ahmet Dogan and Elena Campos-S{\'a}nchez and Green, {Michael R.} and Alizadeh, {Ash A.} and Cesar Cobaleda and Isidro S{\'a}nchez-Garc{\'i}a and Lossos, {Izidore S.}",

note = "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 Le{\'o}n (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 Investigaci{\'o}n en Celulas Madre Tumorales en Cancer de Mama, supported by Obra Social Kutxa y Conserjer{\'i}a de Sanidad de la Junta de Castilla y Leon.",

year = "2013",

doi = "10.1038/ncomms2334",

language = "English (US)",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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 -

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

Abstract

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