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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (26), p.10534-10539
Main Authors: Vicente-Dueñas, Carolina, Fontán, Lorena, Gonzalez-Herrero, Ines, Romero-Camarero, Isabel, Segura, Victor, Aznar, M. Angela, Alonso-Escudero, Esther, Campos-Sanchez, Elena, Ruiz-Roca, Lucía, Barajas-Diego, Marcos, Sagardoy, Ainara, Martinez-Ferrandis, Jose I, Abollo-Jimenez, Fernando, Bertolo, Cristina, Peñuelas, Ivan, Garcia-Criado, Francisco J, García-Cenador, María B, Tousseyn, Thomas, Agirre, Xabier, Prosper, Felipe, Garcia-Bragado, Federico, McPhail, Ellen D, Lossos, Izidore S, Du, Ming-Qing, Flores, Teresa, Hernandez-Rivas, Jesus M, Gonzalez, Marcos, Salar, Antonio, Bellosillo, Beatriz, Conde, Eulogio, Siebert, Reiner, Sagaert, Xavier, Cobaleda, Cesar, Sanchez-Garcia, Isidro, Martinez-Climent, Jose A
Format: Article
Language:English
Subjects:
animal models
Animals
B cell lymphoma
B lymphocytes
Biological Sciences
Caspases - genetics
cell viability
Cells
chromosome translocation
Gene expression
Genes
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
human diseases
Humans
linkage (genetics)
Lymphocytes
Lymphoma
Lymphoma - pathology
Mice
Mice, Transgenic
Mucosa associated lymphoid tissue lymphoma
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
neoplasm cells
Neoplasm Proteins - genetics
NF-kappa B - metabolism
Oncogenes
Pathogenesis
Proteins
proteolysis
Rodents
Signatures
Stem cells
tissues
transcription factor NF-kappa B
Transcription, Genetic
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1204127109