Suchergebnisse

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. ; Spanish Ministry of Science and Innovation; Consejo Superior de Investigaciones Científicas; Junta de Castilla y León; Fundación Ramón Areces; Affymetrix Collaboration in Cancer; Navarra Government; European Union Fondo Europeo de Desarrollo Regional (FEDER) program ; Peer Reviewed

PMCID: PMC3545406.-- et al. ; The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation. ; National Institutes of Health (NIH) grants NIH CA109335 and NIH CA122105; the Dwoskin Family Foundations; NIH P01 CA34233 FEDER and by MICINN (SAF2009-08803 and SAF2012-32810 to ISG); Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010); MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017); Sandra Ibarra Foundation; Group of Excellence Grant (GR15) from Junta de Castilla y Leon; the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Programme) ; Peer Reviewed