Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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. Keywords: Genetic modification, wt vs. transgenic, disease analysis, MALT lymphoma 9 samples were analized of which 5 were splenic lymphomas from Sca1-MALT1 transgenic mice and 4 were spleens from WT mice.

ORGANISM(S): Mus musculus

SUBMITTER: Victor Segura

PROVIDER: E-GEOD-25637 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Vicente-Dueñas Carolina C Fontán Lorena L Gonzalez-Herrero Ines I Romero-Camarero Isabel I Segura Victor V Aznar M Angela MA Alonso-Escudero Esther E Campos-Sanchez Elena E Ruiz-Roca Lucía L Barajas-Diego Marcos M Sagardoy Ainara A Martinez-Ferrandis Jose I JI Abollo-Jimenez Fernando F Bertolo Cristina C Peñuelas Ivan I Garcia-Criado Francisco J FJ García-Cenador María B MB Tousseyn Thomas T Agirre Xabier X Prosper Felipe F Garcia-Bragado Federico F McPhail Ellen D ED Lossos Izidore S IS Du Ming-Qing MQ Flores Teresa T Hernandez-Rivas Jesus M JM Gonzalez Marcos M Salar Antonio A Bellosillo Beatriz B Conde Eulogio E Siebert Reiner R Sagaert Xavier X Cobaleda Cesar C Sanchez-Garcia Isidro I Martinez-Climent Jose A JA

Proceedings of the National Academy of Sciences of the United States of America 20120611 26

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 ...[more]

PMID: 22689981

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Project description:MALT lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-ÎºB pathway. Gastric MALT lymphomas harboring such translocation do not respond to H. pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 24 MALT lymphomas (15 translocation-positive, 9 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-ÎºB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-ÎºB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-ÎºB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors. This study compares MALT with other lymphomas, namely follicular lymphomas (FL) and mantle cell lymphomas (MCL), and investigates the molecular mechanisms of the lymphomagenesis between translocation-positive versus -negative MALT lymphoma cases in order to derive the pathways leading to MALT lymphoma pathogenesis. The study uses fresh frozen tissues from 24 MALT lymphoma cases with 7 FL and 7 MCL. Samples were run on the HG-U133A, HG-U133B, and HG-U133 plus2 GeneChips.

Dataset Information

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

Publications

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

Similar Datasets

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