Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice.

Abstract

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.

• Authors: Carolina Vicente-Dueñas, Lorena Fontán, Ines Gonzalez-Herrero, Isabel Romero-Camarero, Victor Segura, M Angela Aznar, Esther Alonso-Escudero, Elena Campos-Sanchez, Lucía Ruiz-Roca, Marcos Barajas-Diego, Ainara Sagardoy, Jose I Martinez-Ferrandis, Fernando Abollo-Jimenez, Cristina Bertolo, Ivan Peñuelas, Francisco J Garcia-Criado, María B García-Cenador, Thomas Tousseyn, Xabier Agirre, Felipe Prosper, Federico Garcia-Bragado, Ellen D McPhail, Izidore S Lossos, Ming-Qing Du, Teresa Flores, Jesus M Hernandez-Rivas, Marcos Gonzalez, Antonio Salar, Beatriz Bellosillo, Eulogio Conde, Reiner Siebert, Xavier Sagaert, Cesar Cobaleda, Isidro Sanchez-Garcia, Jose A Martinez-Climent
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 26 Pg. 10534-9 (Jun 26 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22689981 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Neoplasm Proteins
• Caspases
• MALT1 protein, human
• Malt1 protein, mouse
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Topics

• Animals
• Caspases (genetics)
• Hematopoietic Stem Cells (metabolism)
• Humans
• Lymphoma (pathology)
• Mice
• Mice, Transgenic
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
• NF-kappa B (metabolism)
• Neoplasm Proteins (genetics)
• Oncogenes
• Transcription, Genetic