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

被引：62

作者：

Vicente-Duenas, Carolina ^{[1
,2
]}

Fontan, Lorena ^{[3
]}

Gonzalez-Herrero, Ines ^{[1
,2
]}

Romero-Camarero, Isabel ^{[1
,2
]}

Segura, Victor ^{[4
]}

Angela Aznar, M. ^{[3
]}

Alonso-Escudero, Esther ^{[1
,2
]}

Campos-Sanchez, Elena ^{[5
]}

Ruiz-Roca, Lucia ^{[1
,2
]}

Barajas-Diego, Marcos ^{[1
,2
]}

Sagardoy, Ainara ^{[3
]}

Martinez-Ferrandis, Jose I. ^{[3
]}

Abollo-Jimenez, Fernando ^{[5
]}

Bertolo, Cristina ^{[3
]}

Penuelas, Ivan ^{[6
]}

Garcia-Criado, Francisco J. ^{[7
]}

Garcia-Cenador, Maria B. ^{[7
]}

Tousseyn, Thomas ^{[8
]}

Agirre, Xabier ^{[3
,9
]}

Prosper, Felipe ^{[3
,9
]}

Garcia-Bragado, Federico ^{[10
]}

McPhail, Ellen D. ^{[11
]}

Lossos, Izidore S. ^{[12
]}

Du, Ming-Qing ^{[13
]}

Flores, Teresa ^{[16
]}

Hernandez-Rivas, Jesus M. ^{[14
,15
]}

Gonzalez, Marcos ^{[14
,15
]}

Salar, Antonio ^{[17
]}

Bellosillo, Beatriz ^{[18
]}

Conde, Eulogio ^{[19
]}

Siebert, Reiner ^{[20
]}

Sagaert, Xavier ^{[8
]}

Cobaleda, Cesar ^{[5
]}

Sanchez-Garcia, Isidro ^{[1
,2
]}

Martinez-Climent, Jose A. ^{[3
]}

机构：

[1] Univ Salamanca, CSIC, Expt Therapeut & Translat Oncol Program, IBMCC, Salamanca 37007, Spain

[2] Univ Salamanca, CSIC, Inst Biomed Res Salamanca IBSAL, Salamanca 37007, Spain

[3] Univ Navarra, Ctr Appl Med Res CIMA, Div Oncol, Pamplona 31008, Spain

[4] Univ Navarra, Ctr Appl Med Res, Bioinformat Unit, Pamplona 31008, Spain

[5] Univ Autonoma Madrid, CSIC, Dept Dev & Differentiat, CBMSO, E-28049 Madrid, Spain

[6] Univ Navarra Clin, Dept Nucl Med, Pamplona 31008, Spain

[7] Univ Salamanca, Dept Surg, Salamanca 37007, Spain

[8] Katholieke Univ Leuven, Ctr Translat Cell & Tissue Res, B-3000 Louvain, Belgium

[9] Univ Navarra, Univ Navarra Clin, Dept Hematol, Pamplona 31008, Spain

[10] Hosp Virgen Camino, Dept Pathol, Pamplona 31008, Spain

[11] Mayo Clin, Dept Lab Med & Pathol, Div Hematopathol, Rochester, MN 55905 USA

[12] Univ Miami, Ctr Comprehens Canc, Div Hematol Oncol, Miami, FL 33136 USA

[13] Univ Cambridge, Dept Pathol, Div Mol Histopathol, Cambridge CB2 1, England

[14] Univ Salamanca, IBMCC CSIC, Salamanca 37007, Spain

[15] Univ Salamanca, IBSAL Univ Hosp, Dept Hematol, Salamanca 37007, Spain

[16] Univ Salamanca, Clin Hosp, Dept Pathol, Salamanca 37007, Spain

[17] Hosp del Mar, IMIM, Dept Clin Hematol, Barcelona 08003, Spain

[18] Hosp del Mar, IMIM, Canc Res Program, Dept Pathol, Barcelona 08003, Spain

[19] Hosp Univ Marques de Valdecilla, Dept Hematol, Santander 39011, Spain

[20] Univ Kiel, Inst Human Genet, D-24105 Kiel, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 26期

关键词：

molecular-directed therapy; transgenic mice; cancer stem cells; tumor reprogramming; MOLECULAR SUBTYPES; TISSUE LYMPHOMAS; STEM-CELL; ABNORMALITIES; GENE;

D O I：

10.1073/pnas.1204127109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：10534 / 10539

页数：6

共 26 条

[1] Selective expansion of marginal zone B cells in Eμ-API2-MALT1 mice is linked to enhanced IκB kinase γ polyubiquitination [J].

Baens, Mathijs ;

Fevery, Sabine ;

Sagaert, Xavier ;

Noels, Heidi ;

Hagens, Sofie ;

Broeckx, Vicky ;

Billiau, An D. ;

De Wolf-Peeters, Christiane ;

Marynen, Peter .

CANCER RESEARCH, 2006, 66 (10) :5270-5277

[2] A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy [J].

Choi, William W. L. ;

Weisenburger, Dennis D. ;

Greiner, Timothy C. ;

Piris, Miguel A. ;

Banham, Alison H. ;

Delabie, Jan ;

Braziel, Rita M. ;

Geng, Huimin ;

Iqbal, Javeed ;

Lenz, Georg ;

Vose, Julie M. ;

Hans, Christine P. ;

Fu, Kai ;

Smith, Lynette M. ;

Li, Min ;

Liu, Zhongfeng ;

Gascoyne, Randy D. ;

Rosenwald, Andreas ;

Ott, German ;

Rimsza, Lisa M. ;

Campo, Elias ;

Jaffe, Elaine S. ;

Jaye, David L. ;

Staudt, Louis M. ;

Chan, Wing C. .

CLINICAL CANCER RESEARCH, 2009, 15 (17) :5494-5502

[3] T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20 [J].

Coornaert, Beatrice ;

Baens, Mathijs ;

Heyninck, Karen ;

Bekaert, Tine ;

Haegman, Mira ;

Staal, Jens ;

Sun, Lijun ;

Chen, Zhijian J. ;

Marynen, Peter ;

Beyaert, Rudi .

NATURE IMMUNOLOGY, 2008, 9 (03) :263-271

[4] The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas [J].

Dierlamm, J ;

Baens, M ;

Wlodarska, I ;

Stefanova-Ouzounova, M ;

Hernandez, JM ;

Hossfeld, DK ;

De Wolf-Peeters, C ;

Hagemeijer, A ;

Van den Berghe, H ;

Marynen, P .

BLOOD, 1999, 93 (11) :3601-3609

[5] THE ACCUMULATION OF P53 ABNORMALITIES IS ASSOCIATED WITH PROGRESSION OF MUCOSA-ASSOCIATED LYMPHOID-TISSUE LYMPHOMA [J].

DU, MQ ;

PENG, HZ ;

SINGH, N ;

ISAACSON, PG ;

PAN, LX .

BLOOD, 1995, 86 (12) :4587-4593

[6] Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma [J].

Dunleavy, Kieron ;

Pittaluga, Stefania ;

Czuczman, Myron S. ;

Dave, Sandeep S. ;

Wright, George ;

Grant, Nicole ;

Shovlin, Margaret ;

Jaffe, Elaine S. ;

Janik, John E. ;

Staudt, Louis M. ;

Wilson, Wyndham H. .

BLOOD, 2009, 113 (24) :6069-6076

[7] Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma [J].

Farinha, P ;

Gascoyne, RD .

JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (26) :6370-6378

[8] Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells [J].

Ferch, Uta ;

Kloo, Bernhard ;

Gewies, Andreas ;

Pfaender, Vera ;

Duewel, Michael ;

Peschel, Christian ;

Krappmann, Daniel ;

Ruland, Juergen .

JOURNAL OF EXPERIMENTAL MEDICINE, 2009, 206 (11) :2313-2320

[9] Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma [J].

Hailfinger, Stephan ;

Lenz, Georg ;

Ngo, Vu ;

Posvitz-Fejfar, Anita ;

Rebeaud, Fabien ;

Guzzardi, Montserrat ;

Penas, Eva-Maria Murga ;

Dierlamm, Judith ;

Chan, Wing C. ;

Staudt, Louis M. ;

Thome, Margot .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (47) :19946-19951

[10] Timeline - MALT lymphoma: from morphology to molecules [J].

Isaacson, PG ;

Du, MQ .

NATURE REVIEWS CANCER, 2004, 4 (08) :644-653

← 1 2 3 →