Endothelial progenitor cells display clonal restriction in multiple myeloma
Author(s)
Date
2006Source Title
BMC Cancer
Print ISSN
1471-2407
Publisher
BioMed Central Ltd.
Volume
6
Pages
1 - 12
Language
English
Type
ArticleItem Usage Stats
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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 receptorImmunoglobulin 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