A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors

Carolina Vicente-Duenas, Isabel Romero-Camarero, Inés González-Herrero, Esther Alonso-Escudero, Fernando Abollo-Jiménez, Xiaoyu Jiang, Norma C. Gutierrez, Alberto Orfao, Nieves Marín, Luisa María Villar, Ma Carmen Fernández Criado, Belnn Pintado, Teresa Flores, Diego Alonso-López, Javier De Las Rivas, Rafael Jiménez, Francisco Javier García Criado, María Begona García Cenador, Izidore S. Lossos, César CobaledaIsidro Sánchez-García

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Understanding the cellular origin of cancer can help to improve disease prevention and therapeutics. Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of Maf oncogenes (associated to human plasma cell neoplasias) is targeted to mouse B cells, the resulting animals fail to reproduce the human disease. Here, to explore early cellular changes that might take place in the development of plasma cell neoplasias, we engineered transgenic mice to express MafB in haematopoietic stem/progenitor cells (HS/PCs). Unexpectedly, we show that plasma cell neoplasias arise in the MafB-transgenic mice. Beyond their clinical resemblance to human disease, these neoplasias highly express genes that are known to be upregulated in human multiple myeloma. Moreover, gene expression profiling revealed that MafB-expressing HS/PCs were more similar to B cells and tumour plasma cells than to any other subset, including wild-type HS/PCs. Consistent with this, genome-scale DNA methylation profiling revealed that MafB imposes an epigenetic program in HS/PCs, and that this program is preserved in mature B cells of MafB-transgenic mice, demonstrating a novel molecular mechanism involved in tumour initiation. Our findings suggest that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias.

Original languageEnglish (US)
Pages (from-to)3704-3717
Number of pages14
JournalEMBO Journal
Volume31
Issue number18
DOIs
StatePublished - Sep 12 2012

Keywords

  • cancer therapy
  • MafB
  • multiple myeloma mouse model
  • oncogenes
  • reprogramming stem cells

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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    Vicente-Duenas, C., Romero-Camarero, I., González-Herrero, I., Alonso-Escudero, E., Abollo-Jiménez, F., Jiang, X., Gutierrez, N. C., Orfao, A., Marín, N., Villar, L. M., Criado, M. C. F., Pintado, B., Flores, T., Alonso-López, D., De Las Rivas, J., Jiménez, R., Criado, F. J. G., Cenador, M. B. G., Lossos, I. S., ... Sánchez-García, I. (2012). A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors. EMBO Journal, 31(18), 3704-3717. https://doi.org/10.1038/emboj.2012.227