A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors.
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.
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Spain.
Carolina
C
Vicente-Dueñas
Isabel
I
Romero-Camarero
Inés
I
González-Herrero
Esther
E
Alonso-Escudero
Fernando
F
Abollo-Jiménez
Xiaoyu
X
Jiang
Norma C
NC
Gutierrez
Alberto
A
Orfao
Nieves
N
Marín
Luisa María
LM
Villar
Ma Carmen Fernández
MC
Criado
Belén
B
Pintado
Teresa
T
Flores
Diego
D
Alonso-López
Javier
J
De Las Rivas
Rafael
R
Jiménez
Francisco Javier García
FJ
Criado
María Begoña García
MB
Cenador
Izidore S
IS
Lossos
César
C
Cobaleda
Isidro
I
Sánchez-García
D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000950:Antigens, Ly / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D019175:DNA Methylation; D018076:DNA, Complementary / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051258:MafB Transcription Factor / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic
D018952:Antigens, CD34; D000950:Antigens, Ly; D018076:DNA, Complementary; C074650:Ly6a protein, mouse; C490407:MAFB protein, human; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D008565:Membrane Proteins