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

      1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 2 , 4 , 2 , 5 , 6 , 6 , 7 , 8 , 2 , 9 , 10 , 10 , 11 , 2 , 12 , 2 , 13 , 2 , 13 , 3 , 14 , a , 15 , b , 1 , 2

      The EMBO Journal

      Nature Publishing Group

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

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          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.

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          Most cited references 54

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          Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.

          An emerging concept in the field of cancer biology is that a rare population of 'tumour stem cells' exists among the heterogeneous group of cells that constitute a tumour. This concept, best described with human leukaemia, indicates that stem cell function (whether normal or neoplastic) might be defined by a common set of critical genes. Here we show that the Polycomb group gene Bmi-1 has a key role in regulating the proliferative activity of normal stem and progenitor cells. Most importantly, we provide evidence that the proliferative potential of leukaemic stem and progenitor cells lacking Bmi-1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukaemia. Complementation studies showed that Bmi-1 completely rescues these proliferative defects. These studies therefore indicate that Bmi-1 has an essential role in regulating the proliferative activity of both normal and leukaemic stem cells.
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            The molecular classification of multiple myeloma.

            To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
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              Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets.

              Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
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                Author and article information

                Journal
                EMBO J
                EMBO J
                The EMBO Journal
                Nature Publishing Group
                0261-4189
                1460-2075
                12 September 2012
                17 August 2012
                17 August 2012
                : 31
                : 18
                : 3704-3717
                Affiliations
                [1 ]simpleExperimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca , Salamanca, Spain
                [2 ]simpleInstitute of Biomedical Research of Salamanca (IBSAL) , Salamanca, Spain
                [3 ]simpleDivision of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami , Miami, FL, USA
                [4 ]simpleServicio de Hematología. Hospital Universitario de Salamanca , Salamanca, Spain
                [5 ]simpleServicio de Citometría and Departamento de Medicina, Universidad de Salamanca , Salamanca, Spain
                [6 ]simpleServicio de Inmunología, Hospital Ramón y Cajal , Madrid, Spain
                [7 ]simpleFacultad de Medicina, Universidad Autónoma , Madrid, Spain
                [8 ]simpleGenetically Engineered Mouse Facility, CNB-CSIC , Madrid, Spain
                [9 ]simpleDepartamento de Anatomía Patológica, Universidad de Salamanca , Salamanca, Spain
                [10 ]simpleBioinformatics Unit, Cancer Research Center (CSIC-USAL) , Salamanca, Spain
                [11 ]simpleBioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL) , Salamanca, Spain
                [12 ]simpleDepartamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental , Salamanca, Spain
                [13 ]simpleDepartamento de Cirugía, Universidad de Salamanca , Salamanca, Spain
                [14 ]simpleDepartment of Molecular and Cellular Pharmacology, University of Miami , Miami, FL, USA
                [15 ]simpleCentro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid , Madrid, Spain
                Author notes
                [a ]simpleCentro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid , c/Nicolás Cabrera, no 1, Campus de Cantoblanco, Madrid 28049, Spain. Tel.:+34 911964692; Fax:+34 911964420; E-mail: ccobaleda@ 123456cbm.uam.es
                [b ]simpleExperimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca , Campus M. de Unamuno s/n, Salamanca 37007, Spain. Tel.:+34 923238403; Fax:+34 923294813; E-mail: isg@ 123456usal.es
                Article
                emboj2012227
                10.1038/emboj.2012.227
                3442275
                22903061
                Copyright © 2012, European Molecular Biology Organization

                This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial No Derivative Works 3.0 Unported License, which permits distribution and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

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