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: 8.19). 12/2005; 11(21):7599-606. DOI: 10.1158/1078-0432.CCR-05-0523
Source: PubMed

ABSTRACT 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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    • "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 · 4.96 Impact Factor
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    • "Finally, malignant plasma cells display high plasticity and are capable, after long-term interaction with other components of the BM microenvironment, to reprogram their gene array as well as to turn back to a more immature phenotype including low levels of CD19 but lacking both CD38 and CD138 molecules. In addition, these cells resemble the plasmablastic morphology, thus supporting a " de-differentiation " theory (Yaccoby, 2005) rather than the existence of a subset of CSCs within the MM bulk during early phase of its development. Fig. 2 shows the detection of putative CSCs in a representative bone biopsy from a patient with MM. "
    Cancer Stem Cells - The Cutting Edge, 08/2011; , ISBN: 978-953-307-580-8
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    • "Similarly, our group has performed GEP between new and relapsed patients, and between CD138 -and CD138 + MM cell lines and have found promising targets that seem to be involved in drug resistance and self-renewal [84] [87] [90]. Targeting of MMSC will also have a different therapeutic profile than traditional drugs, and attacking the bulk tumor, the stem cell niche, and the microenvironment needs to be considered especially if the more differentiated bulk tumor might have the capacity to revert to the stem cell-like phenotype [31] [34]. "
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    ABSTRACT: Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and affects about 4 in 100,000 Americans. Even though much progress has been made in MM therapy, MM remains an incurable disease for the vast majority of patients. The existence of MM stem cell is considered one of the major causes of MM drug-resistance, leading to relapse. This highlights the importance and urgency of developing approaches to target MM stem cells. However, very little is known about the molecular characteristics of the MM stem cells, which makes it difficult to target MM stem cells therapeutically. Evidence of the existence of a myeloma stem cell has been provided by Matsui et al. showing that the CD138- and CD20+ fraction, which is a minor population of the MM cells, has a greater clonogenic potential and has the phenotype of a memory B-cell (CD19+, CD27+). In this review, we report recent progress of cell surface markers in cancer stem cells, especially in myeloma and the molecular mechanisms related to drug resistance and myeloma disease progression.
    01/2011; 1(2):135-45.
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