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

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

1. Carolina Vicente-Dueñas^a,¹,
2. Lorena Fontán^b,¹,
3. Ines Gonzalez-Herrero^a,
4. Isabel Romero-Camarero^a,
5. Victor Segura^c,
6. M. Angela Aznar^b,
7. Esther Alonso-Escudero^a,
8. Elena Campos-Sanchez^d,
9. Lucía Ruiz-Roca^a,
10. Marcos Barajas-Diego^a,
11. Ainara Sagardoy^b,
12. Jose I. Martinez-Ferrandis^b,
13. Fernando Abollo-Jimenez^d,
14. Cristina Bertolo^b,
15. Ivan Peñuelas^e,
16. Francisco J. Garcia-Criado^f,
17. María B. García-Cenador^f,
18. Thomas Tousseyn^g,
19. Xabier Agirre^b,^h,
20. Felipe Prosper^b,^h,
21. Federico Garcia-Bragadoⁱ,
22. Ellen D. McPhail^j,
23. Izidore S. Lossos^k,
24. Ming-Qing Du^l,
25. Teresa Flores^m,
26. Jesus M. Hernandez-Rivasⁿ,
27. Marcos Gonzalezⁿ,
28. Antonio Salar^o,
29. Beatriz Bellosillo^p,
30. Eulogio Conde^q,
31. Reiner Siebert^r,
32. Xavier Sagaert^g,
33. Cesar Cobaleda^d,
34. Isidro Sanchez-Garcia^a,²,³, and
35. Jose A. Martinez-Climent^b,²,³

+ Author Affiliations

1. ^aExperimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer (IBMCC) and Institute of Biomedical Research of Salamanca (IBSAL), Consejo Superior de Investigaciones Cientificas (CSIC)/University of Salamanca, 37007 Salamanca, Spain;
2. ^bDivision of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
3. ^cBioinformatics Unit, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
4. ^dDepartment of Development and Differentiation, Centro de Biologia Molecular Severo Ochoa (CBMSO), CSIC/Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain;
5. ^eDepartment of Nuclear Medicine, Clinica Universidad de Navarra, 31008 Pamplona, Spain;
6. ^fSurgery Department, University of Salamanca, 37007 Salamanca, Spain;
7. ^gCentre for Translational Cell and Tissue Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;
8. ^hDepartment of Hematology, Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
9. ⁱDepartment of Pathology, Hospital Virgen del Camino, 31008 Pamplona, Spain;
10. ^jDivision of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;
11. ^kDivision of Hematology-Oncology, University of Miami Comprehensive Cancer Center, University of Miami, Miami, FL 33136;
12. ^lDivision of Molecular Histopathology, Department of Pathology, Cambridge University, Cambridge CB2 1, United Kingdom;
13. ^mDepartment of Pathology, Clinic Hospital, University of Salamanca, 37007 Salamanca, Spain;
14. ⁿDepartment of Hematology, IBSAL-University Hospital and IBMCC-CSIC, University of Salamanca, 37007 Salamanca, Spain;
15. ^oDepartment of Clinical Hematology, Institut Municipal d’Investigacions Mèdiques (IMIM), Hospital del Mar, 08003 Barcelona, Spain;
16. ^pDepartment of Pathology, Cancer Research Program, IMIM, Hospital del Mar, 08003 Barcelona, Spain;
17. ^qDepartment of Hematology, Hospital Universitario Marques de Valdecilla, 39011 Santander, Spain; and
18. ^rInstitute of Human Genetics, Christian-Albrechts-University Kiel, 24105 Kiel, Germany

1. Edited* by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved May 16, 2012 (received for review March 13, 2012)
2. ↵ ¹C.V.-D. and L.F. contributed equally to this work.
3. ↵ ²I.S.-G. and J.A.M.-C. contributed equally to this work.

Abstract

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.

• molecular-directed therapy
• transgenic mice
• cancer stem cells
• tumor reprogramming

Footnotes

• ↵ ³To whom correspondence may be addressed. E-mail: isg@usal.es or jamcliment@unav.es.

• Author contributions: C.V.-D., L.F., C.C., I.S.-G., and J.A.M.-C. designed research; C.V.-D., L.F., I.G.-H., I.R.-C., V.S., M.A.A., E.A.-E., E.C.-S., L.R.-R., M.B.-D., A. Sagardoy, J.I.M.-F., F.A.-J., C.B., I.P., F.J.G.-C., M.B.G.-C., T.T., X.A., F.G.-B., M.-Q.D., J.M.H.-R., B.B., R.S., X.S., C.C., I.S.-G., and J.A.M.-C. performed research; E.D.M., I.S.L., A. Salar, and E.C. contributed new reagents/analytic tools; C.V.-D., L.F., T.T., F.P., F.G.-B., M.-Q.D., T.F., J.M.H.-R., M.G., B.B., X.S., C.C., I.S.-G., and J.A.M.-C. analyzed data; L.F. and V.S. analyzed the microarray data; F.P., E.D.M., I.S.L., M.-Q.D., J.M.H.-R., M.G., A. Salar, E.C., R.S., and X.S. provided human samples; T.T., F.G.-B., T.F., and X.S. analyzed mouse and human histopathology data; C.C., I.S.-G., and J.A.M.-C. coordinated and supervised the project; and C.V.-D., L.F., C.C., I.S.-G., and J.A.M.-C. wrote the paper.
• The authors declare no conflict of interest.
• ↵*This Direct Submission article had a prearranged editor.
• Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE25636–GSE25639 and GSE34015).
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1204127109/-/DCSupplemental.

Freely available online through the PNAS open access option.