Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2010 Sep 1;5(9):e12487. doi: 10.1371/journal.pone.0012487.
Plasma 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 FINDINGS: Human 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.
Telomerase 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.
浆细胞构成多发性骨髓瘤（MM）中大多数肿瘤细胞，但缺乏持续克隆生长的潜力。相比之下，克隆型 B 细胞可以植入并在免疫缺陷小鼠中重现疾病，这表明它们是 MM 癌症干细胞（CSC）。这些肿瘤起始 B 细胞还具有与正常干细胞相同的功能特征，如耐药性和自我更新潜力。因此，调节正常干细胞的细胞过程可能成为 MM 的治疗靶点。端粒酶活性是维持正常成体干细胞所必需的，我们研究了端粒酶抑制剂imetelstat 对 MM CSC 的活性。此外，我们进行了长期和短期抑制研究，以检查端粒长度依赖性和非依赖性活性。
方法/主要发现：从细胞系和原发性临床标本中分离出人 MM CSC，并使用imetelstat 进行处理，imetelstat 是端粒酶逆转录酶活性的特异性抑制剂。暴露于 imetelstat 2 周可导致端粒长度显著缩短，并抑制体外和体内克隆性 MM 生长。除了这些相对长期的作用外，imetelstat 治疗 72 小时可抑制克隆性生长，这与基于浆细胞抗原 CD138 和干细胞标记物醛脱氢酶的 MM CSC 分化有关。MM CSC 的短期治疗还降低了通常由干细胞表达的基因的表达（OCT3/4、SOX2、NANOG 和 BMI1），这是通过定量实时 PCR 揭示的。
端粒酶活性调节 MM CSC 的克隆生长。此外，长期和短期端粒酶抑制后 MM 生长的减少表明，它通过端粒长度依赖性和非依赖性机制影响 CSC。
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