Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients

Wallace, Stephanie R.; Oken, Martin M.; Lunetta, Kathryn L.; Panoskaltsis‐Mortari, Angela; Masellis, Anna M.

doi:10.1002/1097-0142(20010401)91:7<1219::aid-cncr1122>3.0.co;2-1

Cited by 104 publications

(94 citation statements)

References 41 publications

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“…For instance, MSCs from patients with myelodysplastic syndrome and severe aplastic anemia show impaired immunomodulatory functions in which they fail to properly elicit T cell suppression (14,15). Multiple myeloma and systemic lupus erythematosus have also been associated with deficiencies in cytokine production in MSCs (16,17). Also, the mechanisms by which APC functions are regulated in MSCs would be relevant to hemopoiesis.…”

supporting

confidence: 92%

“…The immune biology of MSCs and the mechanisms by which these stem cells revert to immune suppressor cells could provide insights into the understanding of several immune-mediated dysfunctions, including hematological disorders linked to autoimmune processes (14,16,17). Dysregulated MSC functions have been linked to the pathophysiology of aplastic anemia, which is considered an immune-mediated disorder with increased suppressor T cells, and high levels of IFN-␥ (14).…”

Section: Discussionmentioning

confidence: 99%

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Down-Regulation of MHC II in Mesenchymal Stem Cells at High IFN-γ Can Be Partly Explained by Cytoplasmic Retention of CIITA

Tang

Trzaska

Smirnov

et al. 2008

The Journal of Immunology

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Mesenchymal stem cells (MSCs) are located in postnatal bone marrow, show plasticity, are linked to various bone marrow disorders, exhibit phagocytosis, exert Ag-presenting properties (APC), and are immune suppressive. Unlike professional APCs, MSCs respond bimodally to IFN-γ in MHC-II expression, with expression at 10 U/ml and baseline, and down-regulation at 100 U/ml. The effects at high IFN-γ could not be explained by down-regulation of its receptor, IFN-γRI. In this study, we report on the mechanisms by which IFN-γ regulates MHC-II expression in MSCs. Gel shift assay and Western blot analyses showed dose-dependent increases in activated STAT-1, indicating responsiveness by IFN-γRI. Western blots showed decreased intracellular MHC-II, which could not be explained by decreased transcription of the master regulator CIITA, based on RT-PCR and in situ immunofluorescence. Reporter gene assays with PIII and PIV CIITA promoters indicate constitutive expression of PIII in MSCs and a switch to PIV by IFN-γ, indicating the presence of factors for effect promoter responses. We explained decreased MHC-II at the level of transcription because CIITA protein was observed in the cytosol and not in nuclei at high IFN-γ level. The proline/serine/threonine region of CIITA showed significant decrease in phosphorylation at high IFN-γ levels. An understanding of the bimodal effects could provide insights on bone marrow homeostasis, which could be extrapolated to MSC dysfunction in hematological disorders.

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supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Down-Regulation of MHC II in Mesenchymal Stem Cells at High IFN-γ Can Be Partly Explained by Cytoplasmic Retention of CIITA

Tang

Trzaska

Smirnov

et al. 2008

The Journal of Immunology

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“…19 In contrast, many studies demonstrated an abnormal production of IL-6 that was thought to be dependent on close contact with tumor cells, 20 supporting a paracrine role of this cytokine in tumor cell growth and survival. [21][22][23] The source of IL-6 was considered to be stromal 'elements' without further characterization. Our data demonstrate that MSCs indeed take part in the overproduction of IL-6.…”

Section: Discussionmentioning

confidence: 97%

Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma

et al. 2006

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“…[15][16][17][18] Previous studies suggested that the BMMSCs in MM differ from those of healthy donors. 19,20 In particular, MM BMMSCs expressed less CD106 and fibronectin, and 2.8 times more IL1b as compared with normal BMMSCs 21 and showed abnormal synthesis of hyaluronan. 22,23 Taken together, these data suggest that MM BMMSCs differ from their normal counterparts.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

et al. 2007

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Recent literature suggested that cells of the microenvironment of tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression profiling and phenotypic and functional studies in three groups of individuals: patients with MM, patients with monoclonal gamopathy of undefined significance (MGUS) and healthy agematched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in an MM group. MGUS BMMSCs were interspersed between these two groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs, 46% may account for a tumor-microenvironment cross-talk. Known soluble factors implicated in MM pathophysiologic features (i.e. IL (interleukin)-6, DKK1) were revealed and new ones were found which are involved in angiogenesis, osteogenic differentiation or tumor growth. In particular, GDF15 was found to induce dosedependent growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an overgrowth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, MM BMMSCs are abnormal and could create a very efficient niche to support the survival and proliferation of the myeloma cells.

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Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients

Cited by 104 publications

References 41 publications

Down-Regulation of MHC II in Mesenchymal Stem Cells at High IFN-γ Can Be Partly Explained by Cytoplasmic Retention of CIITA

Down-Regulation of MHC II in Mesenchymal Stem Cells at High IFN-γ Can Be Partly Explained by Cytoplasmic Retention of CIITA

Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

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