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.

[1]  J. S. San Miguel,et al.  A new method for the analysis of plasma cell DNA content in multiple myeloma samples using a CD38/propidium iodide double staining technique. , 1994, Cytometry.

[2]  S. Fox,et al.  Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers , 2009, Nature Medicine.

[3]  Yosuke Tanaka,et al.  Forced expression of Nanog in hematopoietic stem cells results in a gammadeltaT-cell disorder. , 2007, Blood.

[4]  T. Ichisaka,et al.  GENERATION OF GERMLINECOMPETENT INDUCED PLURIPOTENT STEM CELLS , 2007 .

[5]  M. Busslinger,et al.  Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. , 2007, Immunity.

[6]  Xiaolong Wei,et al.  MUC1 Oncoprotein Stabilizes and Activates Estrogen Receptor α , 2006 .

[7]  N. Munshi,et al.  Focus on multiple myeloma. , 2004, Cancer cell.

[8]  S. Bonner-Weir,et al.  Preferential reduction of beta cells derived from Pax6-MafB pathway in MafB deficient mice. , 2008, Developmental biology.

[9]  F. Zhan,et al.  Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. , 2003, Blood.

[10]  A. Hamburger,et al.  Primary bioassay of human myeloma stem cells. , 1977, The Journal of clinical investigation.

[11]  W. Carroll,et al.  Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. , 2012, Blood.

[12]  Natalie Jäger,et al.  Genome-wide mapping of DNA methylation: a quantitative technology comparison , 2010, Nature Biotechnology.

[13]  H. Mitsuya,et al.  Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human. , 2006, Cancer research.

[14]  G. Sauvageau,et al.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells , 2003, Nature.

[15]  M. Busslinger,et al.  Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors , 2007, Nature.

[16]  M. Piris,et al.  Cancer induction by restriction of oncogene expression to the stem cell compartment , 2008, The EMBO journal.

[17]  C. Huff,et al.  Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. , 2008, Cancer research.

[18]  D. Swallow,et al.  MUC1 gene polymorphism in the gastric carcinogenesis pathway , 2001, European Journal of Human Genetics.

[19]  Ashley P Ng,et al.  The sensitivity of CD138 immunostaining of bone marrow trephine specimens for quantifying marrow involvement in MGUS and myeloma, including samples with a low percentage of plasma cells. , 2006, Haematologica.

[20]  G. Peters,et al.  Characterization and chromosome assignment of the human homolog of int-2, a potential proto-oncogene , 1986, Molecular and cellular biology.

[21]  John Crowley,et al.  The molecular classification of multiple myeloma. , 2006, Blood.

[22]  H. Nakauchi,et al.  Self-renewal and lineage restriction of hematopoietic stem cells. , 2003, Current opinion in genetics & development.

[23]  T. D. Hamilton,et al.  Classification of Tumours , 1930, Edinburgh medical journal.

[24]  N. Gutiérrez,et al.  The Progression from MGUS to Smoldering Myeloma and Eventually to Multiple Myeloma Involves a Clonal Expansion of Genetically Abnormal Plasma Cells , 2010, Clinical Cancer Research.

[25]  T. Graf,et al.  MafB is an inducer of monocytic differentiation , 2000, The EMBO journal.

[26]  P. Kastner,et al.  MafB Restricts M-CSF-Dependent Myeloid Commitment Divisions of Hematopoietic Stem Cells , 2009, Cell.

[27]  Anthony B Mak,et al.  The mixed lineage leukemia (MLL) fusion-associated gene AF4 promotes CD133 transcription. , 2012, Cancer research.

[28]  D. Tarin,et al.  Significance of CD44 gene products for cancer diagnosis and disease evaluation , 1992, The Lancet.

[29]  H. Sutherland,et al.  Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). , 2000, Experimental hematology.

[30]  Yosuke Tanaka,et al.  Forced expression of Nanog in hematopoietic stem cells results in a gammadeltaT-cell disorder. , 2007, Blood.

[31]  K. Akashi,et al.  Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. , 2011, Cancer cell.

[32]  T. Graf,et al.  MafB Is an Interaction Partner and Repressor of Ets-1 That Inhibits Erythroid Differentiation , 1996, Cell.

[33]  C. Cobaleda,et al.  Physiological cellular reprogramming and cancer. , 2010, Seminars in cancer biology.

[34]  Zachary D. Smith,et al.  Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling , 2011, Nature Protocols.

[35]  I. Sánchez-García.  Getting to the stem of cancer. , 2010, Seminars in cancer biology.

[36]  Xiaolong Wei,et al.  MUC1 oncoprotein stabilizes and activates estrogen receptor alpha. , 2006, Molecular cell.

[37]  G. Sauvageau,et al.  A Functional Screen to Identify Novel Effectors of Hematopoietic Stem Cell Activity , 2008, Cell.

[38]  Christoph Bock,et al.  Global DNA Demethylation During Mouse Erythropoiesis in Vivo , 2011, Science.

[39]  K. Kataoka,et al.  MafA has strong cell transforming ability but is a weak transactivator , 2003, Oncogene.

[40]  A. Ashworth,et al.  BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. , 2010, Cell stem cell.

[41]  John M. Ashton,et al.  Leukemia stem cells in a genetically defined murine model of blast-crisis CML. , 2007, Blood.

[42]  Jing Liang,et al.  The Molecular Mechanism Governing the Oncogenic Potential of SOX2 in Breast Cancer* , 2008, Journal of Biological Chemistry.

[43]  Satoru Takahashi,et al.  A novel transgenic mouse model of the human multiple myeloma chromosomal translocation t(14;16)(q32;q23). , 2011, Cancer research.

[44]  C. Huff,et al.  Characterization of clonogenic multiple myeloma cells. , 2004, Blood.

[45]  Kenneth C. Anderson,et al.  Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets , 2007, Nature Reviews Cancer.

[46]  R. Bernards,et al.  The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene , 2005, Nature Cell Biology.

[47]  A. Bloem,et al.  Growth factors and antiapoptotic signaling pathways in multiple myeloma , 2005, Leukemia.

[48]  L. Staudt,et al.  Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. , 2004, Cancer cell.

[49]  H. Clevers,et al.  Identification of primary MAFB target genes in multiple myeloma. , 2009, Experimental hematology.

[50]  J. Taipale,et al.  The Hedgehog and Wnt signalling pathways in cancer , 2001, Nature.

[51]  T. Mikkelsen,et al.  Genome-scale DNA methylation maps of pluripotent and differentiated cells , 2008, Nature.

[52]  Gwyn T. Williams.  Programmed cell death: Apoptosis and oncogenesis , 1991, Cell.

[53]  K. Kataoka,et al.  MafB, a new Maf family transcription activator that can associate with Maf and Fos but not with Jun , 1994, Molecular and cellular biology.

[54]  I. Sánchez-García,et al.  Cancer as a reprogramming-like disease: implications in tumor development and treatment. , 2010, Seminars in cancer biology.

[55]  M. Lohuizen,et al.  The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression , 2001, British Journal of Cancer.

[56]  T. Graf,et al.  MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth , 2003, Nature Neuroscience.

[57]  R. Zini,et al.  Virally mediated MafB transduction induces the monocyte commitment of human CD34+ hematopoietic stem/progenitor cells , 2006, Cell Death and Differentiation.

[58]  A. Eychène,et al.  A new MAFia in cancer , 2008, Nature Reviews Cancer.

[59]  John Crowley,et al.  Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. , 2002, Blood.

[60]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[61]  B. Klein,et al.  Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma , 1997, Nature Genetics.

[62]  I. Sánchez-García.  Consequences of chromosomal abnormalities in tumor development. , 1997, Annual review of genetics.

[63]  Jane E. Visvader,et al.  Cells of origin in cancer , 2011, Nature.

[64]  I. González-Herrero,et al.  Essential role for telomerase in chronic myeloid leukemia induced by BCR-ABL in mice , 2012, Oncotarget.

[65]  E. Dzierzak,et al.  Expression of the Ly-6E.1 (Sca-1) transgene in adult hematopoietic stem cells and the developing mouse embryo. , 1997, Development.

[66]  I. Sánchez-García,et al.  B‐cell acute lymphoblastic leukaemia: towards understanding its cellular origin , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[67]  F. Mandelli,et al.  Biology and treatment of multiple myeloma , 1992, Current opinion in oncology.

[68]  T. Ichisaka,et al.  Generation of germline-competent induced pluripotent stem cells , 2007, Nature.

[69]  A. Eychène,et al.  Cell context reveals a dual role for Maf in oncogenesis , 2006, Oncogene.