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Pérdida de la señalización a través de Gα13 en el centro germinal del linfoma derivado de células B
Jagan R Muppidi1, Roland Schmitz2, Jesse A Green3
11] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Department of Medicine, University of California, San Francisco, California 94143, USA [3] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
Nature
|October 3, 2014
Resumen
Las mutaciones en el receptor de esfingosina-1-fosfato-2 (S1PR2) interrumpen sus funciones en el linfoma de células B del centro germinal. Una vía Gα13 normalmente suprime el crecimiento y previene la diseminación, pero con frecuencia se interrumpe en estos linfomas.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- Oncología Oncología.
Sus antecedentes:
- El linfoma difuso de células B grandes del centro germinal de células B (GCB-DLBCL) es un cáncer común con vías de señalización y factores de diseminación poco conocidos.
- El receptor de esfingosina-1-fosfato-2 (S1PR2) normalmente regula el crecimiento y el confinamiento de las células B del centro germinal.
Objetivo del estudio:
- Para investigar el papel de S1PR2 y Gα13 en la patogénesis de GCB-DLBCL.
- Para identificar las vías de señalización interrumpidas en GCB-DLBCL que contribuyen a la diseminación del linfoma.
Principales métodos:
- Ensayos in vitro e in vivo utilizando modelos de ratón y líneas celulares humanas de GCB-DLBCL.
- Secuenciación profunda para identificar mutaciones genéticas.
- Análisis de células deficientes en Gα13 y S1PR2 y en ratones.
Principales resultados:
- Las mutaciones S1PR2 asociadas a GCB-DLBCL perjudican sus funciones inhibidoras de Akt y migración.
- La deficiencia de Gα13 en las células B conduce al desarrollo de linfomas y su diseminación en la linfa y la sangre.
- Las mutaciones en el efector ARHGEF1 de Gα13 también promueven la diseminación de GCB-DLBCL.
- El receptor huérfano P2RY8 fue identificado como un regulador dependiente de Gα13 del crecimiento y confinamiento de las células B.
Conclusiones:
- Una vía dependiente de Gα13 juega un doble papel en la supresión del crecimiento de las células B del centro germinal y la prevención de la diseminación.
- Esta vía se interrumpe con frecuencia en GCB-DLBCL y el linfoma de Burkitt, lo que contribuye a la progresión de la enfermedad.
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