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Title

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

AuthorsVicente-Dueñas, Carolina ; Romero-Camarero, Isabel ; González-Herrero, Inés ; Abollo-Jiménez, Fernando ; Jiang, Xiaoyu; Gutiérrez, Norma Carmen; Orfao, Alberto ; Pintado, Belén; Flores, Teresa; De Las Rivas, Javier ; Jiménez, Rafael; García-Criado, Francisco Javier; García-Cenador, Begoña; Lossos, Izidore S.; Cobaleda, César ; Sánchez García, Isidro
KeywordsCancer therapy
Reprogramming stem cells
Multiple myeloma mouse model
Oncogenes
MafB
Issue Date2012
PublisherNature Publishing Group
CitationEMBO Journal 31(18): 3704- 3717 (2012)
AbstractUnderstanding 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. © 2012 European Molecular Biology Organization | All Rights Reserved.
DescriptionThis article is licensed under a Creative Commons Attribution-NoncommercialNo DerivativeWorks 3.0 Licence.
Publisher version (URL)http://dx.doi.org/10.1038/emboj.2012.227
URIhttp://hdl.handle.net/10261/111499
DOI10.1038/emboj.2012.227
Identifiersissn: 0261-4189
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