Abstract
BackgroundPlasma cells constitute the majority of tumor cells in multiple myeloma (MM) but lack the potential for sustained clonogenic growth. In contrast, clonotypic B cells can engraft and recapitulate disease in immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC). These tumor initiating B cells also share functional features with normal stem cells such as drug resistance and self-renewal potential. Therefore, the cellular processes that regulate normal stem cells may serve as therapeutic targets in MM. Telomerase activity is required for the maintenance of normal adult stem cells, and we examined the activity of the telomerase inhibitor imetelstat against MM CSC. Moreover, we carried out both long and short-term inhibition studies to examine telomere length-dependent and independent activities.Methodology/Principal FindingsHuman MM CSC were isolated from cell lines and primary clinical specimens and treated with imetelstat, a specific inhibitor of the reverse transcriptase activity of telomerase. Two weeks of exposure to imetelstat resulted in a significant reduction in telomere length and the inhibition of clonogenic MM growth both in vitro and in vivo. In addition to these relatively long-term effects, 72 hours of imetelstat treatment inhibited clonogenic growth that was associated with MM CSC differentiation based on expression of the plasma cell antigen CD138 and the stem cell marker aldehyde dehydrogenase. Short-term treatment of MM CSC also decreased the expression of genes typically expressed by stem cells (OCT3/4, SOX2, NANOG, and BMI1) as revealed by quantitative real-time PCR.ConclusionsTelomerase activity regulates the clonogenic growth of MM CSC. Moreover, reductions in MM growth following both long and short-term telomerase inhibition suggest that it impacts CSC through telomere length-dependent and independent mechanisms.
Highlights
Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells that results in anemia, renal insufficiency, and bone disease
Telomerase activity regulates the clonogenic growth of MM cancer stem cell (CSC)
We studied primary clinical specimen from three distinct patients and found that the levels of telomerase activity (TA) were similar in CD138negCD19+CD27+ precursors and CD138+ plasma cells (Figure 1B)
Summary
Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells that results in anemia, renal insufficiency, and bone disease. We previously found that MM cells responsible for producing symptomatic disease in immunodeficient mice phenotypically resemble memory B cells rather than mature plasma cells [2,3] These clonotypic B cells exhibit several attributes that characterize normal stem cells including selfrenewal during serial transplantation and multi-drug resistance. These shared functional properties suggest that specific cellular processes regulating normal stem cells may be active within CSC and serve as potential therapeutic targets. Clonotypic B cells can engraft and recapitulate disease in immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC) These tumor initiating B cells share functional features with normal stem cells such as drug resistance and self-renewal potential. We carried out both long and short-term inhibition studies to examine telomere length-dependent and independent activities
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