期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 26, 页码 10534-10539出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1204127109
关键词
molecular-directed therapy; transgenic mice; cancer stem cells; tumor reprogramming
资金
- Spanish Ministry of Science and Innovation [PI080164]
- Consejo Superior de Investigaciones Cientificas (CSIC) [P.I.E.200920I055, SAF2009-08803, CSD2007-0017, FIS-PI081878, RTICCRD06/0020/0088-0103-0111-0006, PPT-300000-2008-4]
- Junta de Castilla y Leon [SA060A09, CSI007A11-2, SAN/39/2010]
- Fundacion Ramon Areces
- Affymetrix Collaboration in Cancer Program grant
- Spanish Ministry of Science and Innovation
- Navarra Government
- European Union Fondo Europeo de Desarrollo Regional (FEDER)
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-kappa B 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据