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      • Department of Molecular Biology and Genetics
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      Endothelial progenitor cells display clonal restriction in multiple myeloma

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      Author(s)
      Braunstein, M.
      Özçelik, T.
      Baǧişlar, S.
      Vakil, V.
      Smith, E. L. P.
      Dai, K.
      Akyerli, C. B.
      Batuman O. A.
      Date
      2006
      Source Title
      BMC Cancer
      Print ISSN
      1471-2407
      Publisher
      BioMed Central Ltd.
      Volume
      6
      Pages
      1 - 12
      Language
      English
      Type
      Article
      Item Usage Stats
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      144
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      Abstract
      Background: In multiple myeloma (MM), increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI) patterns in female patients by a human androgen receptor assay (HUMARA). In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. Methods: A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (VH). Results: In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these patients, XCI skewing was extreme (≥ 90% expression of a single allele). In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with VH primers resulted in amplification of the same product in EPCs and bone marrow cells in 71 % (n = 5) of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status, unlike patients whose EPCs had random XCI. Conclusion: Our results suggest that EPCs in at least a substantial subpopulation of MM patients are related to the neoplastic clone and that this is an important mechanism for upregulation of tumor neovascularization in MM. © 2006 Braunstein et al; licensee BioMed Central Ltd.
      Keywords
      Androgen receptor
      Immunoglobulin heavy chain
      Adult
      Aged
      Aging
      Allele
      Article
      B lymphocyte
      Bioassay
      Clinical article
      Controlled study
      Endothelium cell
      Female
      Gene amplification
      Gene expression
      Gene rearrangement
      Genetic linkage
      Hair root
      Human
      Human cell
      Male
      Molecular cloning
      Multiple myeloma
      Neovascularization (pathology)
      Peripheral blood mononuclear cell
      Polymerase chain reaction
      Stem cell
      Tumor cell
      Tumor vascularization
      Upregulation
      X chromosome inactivation
      Age Factors
      Clone Cells
      Endothelial Cells
      Female
      Gene Rearrangement
      Humans
      Immunoglobulin Heavy Chains
      Multiple Myeloma
      Multipotent Stem Cells
      Neovascularization, Pathologic
      Prognosis
      Receptors, Androgen
      X Chromosome Inactivation
      Permalink
      http://hdl.handle.net/11693/23779
      Published Version (Please cite this version)
      http://dx.doi.org/10.1186/1471-2407-6-161
      Collections
      • Department of Molecular Biology and Genetics 542
      • Institute of Materials Science and Nanotechnology (UNAM) 2260
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