TY - JOUR
T1 - Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice
AU - Vicente-Dueñas, Carolina
AU - Fontán, Lorena
AU - Gonzalez-Herrero, Ines
AU - Romero-Camarero, Isabel
AU - Segura, Victor
AU - Aznar, M. Angela
AU - Alonso-Escudero, Esther
AU - Campos-Sanchez, Elena
AU - Ruiz-Roca, Lucía
AU - Barajas-Diego, Marcos
AU - Sagardoy, Ainara
AU - Martinez-Ferrandis, Jose I.
AU - Abollo-Jimenez, Fernando
AU - Bertolo, Cristina
AU - Peñuelas, Ivan
AU - Garcia-Criado, Francisco J.
AU - García-Cenador, María B.
AU - Tousseyn, Thomas
AU - Agirre, Xabier
AU - Prosper, Felipe
AU - Garcia-Bragado, Federico
AU - McPhail, Ellen D.
AU - Lossos, Izidore S.
AU - Du, Ming Qing
AU - Flores, Teresa
AU - Hernandez-Rivas, Jesus M.
AU - Gonzalez, Marcos
AU - Salar, Antonio
AU - Bellosillo, Beatriz
AU - Conde, Eulogio
AU - Siebert, Reiner
AU - Sagaert, Xavier
AU - Cobaleda, Cesar
AU - Sanchez-Garcia, Isidro
AU - Martinez-Climent, Jose A.
PY - 2012/6/26
Y1 - 2012/6/26
N2 - 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.
AB - 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.
KW - Cancer stem cells
KW - Molecular-directed therapy
KW - Transgenic mice
KW - Tumor reprogramming
UR - http://www.scopus.com/inward/record.url?scp=84862990370&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862990370&partnerID=8YFLogxK
U2 - 10.1073/pnas.1204127109
DO - 10.1073/pnas.1204127109
M3 - Article
C2 - 22689981
AN - SCOPUS:84862990370
SN - 0027-8424
VL - 109
SP - 10534
EP - 10539
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -