The Phenotypic Plasticity of Myeloma Plasma Cells as Expressed by Dedifferentiation into an Immature, Resilient, and Apoptosis-Resistant Phenotype

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
Clinical Cancer Research (Impact Factor: 8.72). 12/2005; 11(21):7599-606. DOI: 10.1158/1078-0432.CCR-05-0523
Source: PubMed


We previously showed the ability of osteoclasts to support myeloma plasma cell survival and proliferation in vivo and ex vivo. The aim of the current study was to investigate osteoclast-induced phenotypic changes associated with long-term survival of myeloma cells in coculture.
CD138-selected myeloma plasma cells from 16 patients were cocultured with human osteoclasts for up to 20 weeks.
Precultured cells were typically CD45(low/intermediate) CD38(high) CD138(high), CD19(-)CD34(-). After >6 weeks, the phenotype of cocultured myeloma cells consistently shifted to cells expressing CD45(intermediate/high) CD19(low) CD34(low). Expression of CD38 and CD138 were reduced to subpopulations with CD38(intermediate) and CD138(low) levels. Morphologically, cocultured plasma cells became plasmablastic. Blocking interleukin-6 activity did not affect the immature phenotype of myeloma cells. The effect of dexamethasone on myeloma cells cultured alone or in cocultures at baseline and after 6 weeks of coculture was determined. When baseline myeloma cells were cultured alone, dexamethasone significantly increased the percentage of apoptotic cells over the spontaneous rate. Conversely, myeloma cells recovered from cocultures had high survival rates and were resistant to dexamethasone-induced apoptosis. Long-term coculture of normal CD34-expressing hematopoietic stem cells (HSC) resulted in loss of CD34 expression, suggesting a common mechanism for osteoclast-induced myeloma and HSC plasticity.
This study indicates that myeloma cells have plasticity expressed by their ability to reprogram, dedifferentiate, and acquire autonomous survival properties.

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    • "The presence of CD138low/- cells in myeloma is intriguing because it could imply a less differentiated state. In fact, it has been previously reported that the interaction of myeloma cells with different types of cells of the bone marrow microenvironment promotes a reduction of CD138 expression, a less differentiated morphology and an increase of the B-cell associated transcription factor, Bcl6 [15], [16], [38]. Here, we have detected the presence of myeloma cells with low expression of CD138 in the absence of bone marrow microenvironment cells and under these circumstances, the population of CD138low cells does not seem to represent a more immature compartment since it does not express the B-cell associated markers CD19, CD20 and CD27 and it does not show a less differentiated morphology. "
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    ABSTRACT: Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95-99%) and CD138low (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.
    PLoS ONE 03/2014; 9(3):e92378. DOI:10.1371/journal.pone.0092378 · 3.23 Impact Factor
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    • "With regard to the fact that abnormal PC of MM show features of advanced differentiation and mature morphology, it was suspected that a minor population of CD138 À cells is responsible for the origin and sustainability of the tumour mass (Jensen et al, 1993; Bergsagel et al, 1995; Szczepek et al, 1997; Pilarski et al, 2000; Rasmussen et al, 2000; Matsui et al, 2004). However, it was demonstrated that even the dominant population of human CD138 + PC contains clonogenic cells, which have plasticity potential that might be responsible for dedifferentiation and acquiring of stem cell properties (Yata & Yaccoby, 2004; Yaccoby, 2005; Chiron et al, 2012). Despite mature phenotype and low labelling index of myeloma PC, it is striking that these cells express pluripotency factors and stem/progenitor cell markers, such as SOX2, c-Myc (MYC), germline stem cell markers of the MAGE family, haematopoietic progenitor marker CD117 (KIT) or the neural stem cell marker, nestin (NES; Jungbluth et al, research paper 2005; Zhu et al, 2005; Liu et al, 2007; Spisek et al, 2007; Chesi et al, 2008). "
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    ABSTRACT: The stem cell marker nestin (NES) is found in dividing cells of developing and regenerating tissues. Upon terminal differentiation, NES expression is diminished but may be re-expressed following injury or in cancer. Surprisingly, we recently confirmed NES as a tumour-specific marker for mature CD138(+) 38(+) plasma cells (PC) in multiple myeloma (MM). The present study analysed NES expression throughout the spectrum of MM developmental stages, starting with individuals with no haematological malignancy, through monoclonal gammopathy of undetermined significance (MGUS) and MM to plasma cell leukaemia (PCL) and MM cell lines. NES was analysed in bone marrow PC of 163 MM, four PCL and nine MGUS patients, 10 individuals with no haematological malignancy and 6 myeloma cell lines (OPM-2, RPMI-8226, MOLP-8, U-266, EJM, NCI-H929) by flow cytometry and/or real-time polymerase chain reaction or immunochemistry. We observed a tendency of increased NES expression in parallel with disease progression. NES was evaluated as a reliable marker for accurate discrimination between MM patients and the control group. High NES levels were strongly associated with the presence of 1q21 gain. For the first time, NES was demonstrated to predict worse response to conventional therapy/novel agents. These results suggest that NES might become a useful clinical parameter with an important role in MM pathogenesis.
    British Journal of Haematology 12/2013; 164(5). DOI:10.1111/bjh.12689 · 4.71 Impact Factor
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    • "Previous reports have indicated that the bone marrow microenvironment may contribute to CD138 downregulation (13–16). Among various factors in the tumor microenvironment, hypoxia is one of the important factors associated with tumor progression, poor clinical outcomes, dedifferentiation, and formation of cancer stem cell niches in solid tumors (17). "
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    ABSTRACT: Although CD138 expression is a hallmark of plasma cells and myeloma cells, reduced CD138 expression is occasionally found. However, the mechanisms underlying CD138 downregulation in myeloma cells remain unclear. Previous reports suggest that the bone marrow microenvironment may contribute to CD138 downregulation. Among various factors in the tumor microenvironment, hypoxia is associated with tumor progression, poor clinical outcomes, dedifferentiation and the formation of cancer stem cell niches in solid tumors. Since recent findings showed that progression of multiple myeloma (MM) delivers hypoxia within the bone marrow, we hypothesized that CD138 expression may be regulated by hypoxia. In the present study, we examined whether the expression of CD138 and transcription factors occurred in myeloma cells under hypoxic conditions. MM cell lines (KMS-12BM and RPMI 8226) were cultured under normoxic or hypoxic conditions for up to 30 days. Changes in the phenotype and the expression of surface antigens and transcription factors were analyzed using flow cytometry, RT-PCR and western blotting. All-trans retinoic acid (ATRA) was used to examine the phenotypic changes under hypoxic conditions. The expression levels of CD138, CS1 and plasma cell-specific transcription factors decreased under hypoxic conditions, while those of CD20, CXCR4 and B cell-specific transcription factors increased compared with those under normoxic conditions. Stem cell-specific transcription factors were upregulated under hypoxic conditions, while no difference was observed in ALDH activity. The reduced CD138 expression under hypoxic conditions recovered when cells were treated with ATRA, even under hypoxic conditions, along with decreases in the expression of stem cell-specific transcription factor. Interestingly, ATRA treatment sensitized MM cells to bortezomib under hypoxia. We propose that hypoxia induces immature and stem cell-like transcription phenotypes in myeloma cells. Taken together with our previous observation that decreased CD138 expression is correlated with disease progression, the present data suggest that a hypoxic microenvironment affects the phenotype of MM cells, which may correlate with disease progression.
    International Journal of Oncology 10/2013; 43(6). DOI:10.3892/ijo.2013.2134 · 3.03 Impact Factor
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