A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors
| Autor: | Fernando Abollo-Jiménez, Rafael Jiménez, Luisa M. Villar, Nieves Marín, Isidro Sánchez-García, Xiaoyu Jiang, Inés González-Herrero, Alberto Orfao, María Begoña García Cenador, Belén Pintado, Esther Alonso-Escudero, Diego Alonso-López, Francisco Javier García Criado, Teresa Flores, Ma Carmen Fernández Criado, Carolina Vicente-Dueñas, César Cobaleda, Izidore S. Lossos, Norma C. Gutiérrez, Isabel Romero-Camarero, Javier De Las Rivas |
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| Rok vydání: | 2012 |
| Předmět: |
0303 health sciences
MafB Transcription Factor General Immunology and Microbiology General Neuroscience Plasma cell Biology Molecular biology General Biochemistry Genetics and Molecular Biology 3. Good health Gene expression profiling 03 medical and health sciences Haematopoiesis 0302 clinical medicine medicine.anatomical_structure MAFB 030220 oncology & carcinogenesis DNA methylation Cancer research medicine Epigenetics Progenitor cell Molecular Biology 030304 developmental biology |
| Zdroj: | The EMBO Journal. 31:3704-3717 |
| ISSN: | 0261-4189 |
| DOI: | 10.1038/emboj.2012.227 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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