Proceedings of the National Academy of Sciences of the United States of America, 2012. 109(26): p. 10534-9. Epub 2012 Jun 11. PMID:22689981


Vicente-Duenas, C., L. Fontan, I. Gonzalez-Herrero, I. Romero-Camarero, V. Segura, M.A. Aznar, E. Alonso-Escudero, E. Campos-Sanchez, L. Ruiz-Roca, M. Barajas-Diego, A. Sagardoy, J.I. Martinez-Ferrandis, F. Abollo-Jimenez, C. Bertolo, I. Penuelas, F.J. Garcia-Criado, M.B. Garcia-Cenador, T. Tousseyn, X. Agirre, F. Prosper, F. Garcia-Bragado, E.D. McPhail, I.S. Lossos, M.Q. Du, T. Flores, J.M. Hernandez-Rivas, M. Gonzalez, A. Salar, B. Bellosillo, E. Conde, R. Siebert, X. Sagaert, C. Cobaleda, I. Sanchez-Garcia, and J.A. Martinez-Climent.


Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1+Lin− hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.


En el trabajo publicado en la revista PNAS se describe cómo han conseguido reproducir la patología humana en el ratón con una aproximación experimental muy novedosa. La patología estudiada es un tipo de enfermedad denominado Linfoma MALT (linfoma localizado en el tejido linfoide asociado a mucosas) y se ha utilizado una aproximación experimental que permite y limita la expresión de un oncogén (MALT1) a células stem o progenitores dentro del sistema hematopoyético. De este modo, se demuestra por primera vez que es posible reproducir las características histológicas y moleculares de la enfermedad humana en ratón. En consecuencia, se ha generado un nuevo modelo de ratón donde probar posibles terapias frente a esta enfermedad. Por último, estos resultados sugieren que las células stem o progenitores celulares del sistema hematopoyético pueden estar implicadas en la patogénesis de los linfomas en humanos, un hecho hasta ahora no descrito.

imagen noviembre


Este trabajo es el fruto de la colaboración de diferentes grupos de investigación. Los ratones han sido generados y caracterizados por grupos del CSIC pertenecientes al Instituto de Biología Molecular y Celular del Cáncer de Salamanca (CSIC-Universidad de Salamanca) y al Centro de Biologia Molecular Severo Ochoa de Madrid (CBMSO). El modelo de ratón generado ha sido comparado con la patología humana mediante análisis de expresión génica en el Centro de Investigación Médica Aplicada de Pamplona (CIMA).

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