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

Authors' Affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Requests for reprints: Shmuel Yaccoby, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 West Markham, Slot #776, Little Rock, AR 72205. Phone: 501-686-5274; Fax: 501-686-6442; E-mail: yaccobyshmuel{at}uams.edu.

Purpose: 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.

Experimental Design: CD138-selected myeloma plasma cells from 16 patients were cocultured with human osteoclasts for up to 20 weeks.

Results: 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.

Conclusions: This study indicates that myeloma cells have plasticity expressed by their ability to reprogram, dedifferentiate, and acquire autonomous survival properties.

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