A mouse model of deregulation of the malt1 oncogene recapitulates the pathogenesis of human malt lymphoma [Spleen dataset]

Attempts at modeling chromosomal translocations involving MALT1 gene, hallmarks of human mucosa-associated lymphoid tissue (MALT) lymphoma, have failed to reproduce the disease in mice. Here we describe a transgenic model in which MALT1 expression was targeted to mouse hematopoietic stem/progenitor cells. In Sca1-MALT1 mice, MALT1 deregulation activated the NF-kappaB pathway in Sca1+ cells, promoting selective B-cell differentiation and mature lymphocyte accumulation in extranodal tissues, progressively leading to the development of clonal B-cell lymphomas. These tumors recapitulated the histopathological features of human MALT lymphomas, presenting typical lymphoepithelial lesions and plasmacytic differentiation. Transcriptional profiling of Sca1-MALT1 murine lymphomas revealed overlapping molecular signatures with human MALT lymphomas, including MALT1-mediated NFkappaB activation, pro-inflammatory signaling and XBP1-induced plasmacytic differentiation. Moreover, murine Malt1 showed proteolytic activity by cleaving Bcl10 in Sca1-MALT1 lymphomas. Our novel technological approach has allowed modeling human MALT lymphoma in mice, which represent unique tools study MALT lymphoma biology and evaluate anti-MALT1 therapies.

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Vicente-Dueñas C, Fontán L, Gonzalez-Herrero I, Romero-Camarero I, Segura V, Aznar MA, Alonso-Escudero E, Campos-Sanchez E, Ruiz-Roca L, Barajas-Diego M, Sagardoy A, Martinez-Ferrandis JI, Abollo-Jimenez F, Bertolo C, Peñuelas I, Garcia-Criado FJ, García-Cenador MB, Tousseyn T, Agirre X, Prosper F, Garcia-Bragado F, McPhail ED, Lossos IS, Du MQ, Flores T, Hernandez-Rivas JM, Gonzalez M, Salar A, Bellosillo B, Conde E, Siebert R, Sagaert X, Cobaleda C, Sanchez-Garcia I, Martinez-Climent JA