Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice.
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.
Experimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer and Institute of Biomedical Research of Salamanca, Consejo Superior de Investigaciones Cientificas/University of Salamanca, 37007 Salamanca, Spain.
Carolina
C
Vicente-Dueñas
Lorena
L
Fontán
Ines
I
Gonzalez-Herrero
Isabel
I
Romero-Camarero
Victor
V
Segura
M Angela
MA
Aznar
Esther
E
Alonso-Escudero
Elena
E
Campos-Sanchez
Lucía
L
Ruiz-Roca
Marcos
M
Barajas-Diego
Ainara
A
Sagardoy
Jose I
JI
Martinez-Ferrandis
Fernando
F
Abollo-Jimenez
Cristina
C
Bertolo
Ivan
I
Peñuelas
Francisco J
FJ
Garcia-Criado
María B
MB
García-Cenador
Thomas
T
Tousseyn
Xabier
X
Agirre
Felipe
F
Prosper
Federico
F
Garcia-Bragado
Ellen D
ED
McPhail
Izidore S
IS
Lossos
Ming-Qing
MQ
Du
Teresa
T
Flores
Jesus M
JM
Hernandez-Rivas
Marcos
M
Gonzalez
Antonio
A
Salar
Beatriz
B
Bellosillo
Eulogio
E
Conde
Reiner
R
Siebert
Xavier
X
Sagaert
Cesar
C
Cobaleda
Isidro
I
Sanchez-Garcia
Jose A
JA
Martinez-Climent
D000818:Animals; D020169:Caspases / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics*; D009857:Oncogenes; D014158:Transcription, Genetic
D016328:NF-kappa B; D009363:Neoplasm Proteins; D020169:Caspases; C400109:MALT1 protein, human; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein