Referencia

Nature Communications (2013) 4:1338 doi: 10.1038/ncomms2334. PMID: 23299888

Autores

Isabel Romero Camarero, Xiaoyu Jiang, Yasodha Natkunam, Xiaoqing Lu, Carolina Vicente Dueñas, Ines González Herrero, Teresa Flores, Juan Luis García, George McNamara, Christian Kunder, Shuchun Zhao, Víctor Segura, Lorena Fontán , Jose A. Martínez Climent, Francisco Javier García Criado, Jason D. Theis, Ahmet Dogan, Elena Campos Sánchez, Michael R. Green, Ash A. Alizadeh, César Cobaleda, Isidro Sánchez García, Izidore S. Lossos.

Resumen

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.

Descripción

HGAL, de las siglas Human Germinal Center Associated Lymphoma es un gen novedoso que fue descrito por primera vez en el año 2003 y, desde entonces, ha sido relacionado con la supervivencia de pacientes con linfoma B difuso de célula grande y linfoma Hodgkin, pero no se conocía su función biológica. Los resultados publicados en Nature Communications, demuestran, que, la expresión no controlada de HGAL produce una hiperplasia linfoide B. El mecanismo molecular que utiliza HGAL está mediado por la activación de la tirosín-quinasa SyK, que altera la señalización del receptor de los linfocitos B. Estos hallazgos sugieren que los inhibidores de SyK podrían llegar a ser útiles en el tratamiento de esta enfermedad.

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REFERENCIA DEL GRUPO INVESTIGADOR

El trabajo publicado ha sido posible gracias a la colaboración de los grupos del Dr. Izidore Lossos, en la Universidad de Miami e Isidro Sánchez García, del Instituto de Biología Molecular y Celular del Cáncer de Salamanca. El Dr. Lossos fue uno de los descubridores de HGAL, y la investigación desarrollada en su laboratorio se centra en los genes y mecanismos de patogénesis de linfomas humanos. El grupo del Dr. Sánchez García trabaja en entender los mecanismos moleculares que gobiernan la génesis y mantenimiento de las células stem cancerígenas para el desarrollo de nuevos tratamientos frente al cáncer.

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