Telomerase Inhibition Targets Clonogenic Multiple Myeloma Cells through Telomere Length-Dependent and Independent Mechanisms
Telomerase Inhibition Targets Clonogenic Multiple Myeloma Cells through Telomere Length-Dependent and Independent Mechanisms
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DOI：
10.1371/journal.pone.0012487
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发表时间：
2010-09-01
期刊：
影响因子：
3.7
通讯作者：
Matsui, William
中科院分区：
文献类型：
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作者：
Brennan, Sarah K.;Wang, Qiuju;Matsui, William
背景：在多发性骨髓瘤(MM)中，浆细胞是肿瘤细胞的主要成分，但缺乏持续克隆生长的潜能。相比之下，克隆型B细胞可以在免疫缺陷小鼠身上移植和重现疾病，这表明它们是MM癌症干细胞(CSC)。这些启动肿瘤的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能力。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人干细胞所必需的，我们检测了端粒酶抑制剂imetelstat对MM CSC的活性。此外，我们进行了长期和短期的抑制研究，以检测端粒长度依赖和独立的活性。方法/主要发现：从细胞系和原代临床标本中分离人多发性骨髓瘤CSC，并用端粒酶逆转录酶活性的特异性抑制剂imetelstat处理。体外和体内暴露两周后，端粒长度显著缩短，克隆性多发性骨髓瘤生长受到抑制。除了这些相对长期的影响外，72小时的伊美司坦治疗还抑制了与MM CSC分化相关的克隆性生长，这种克隆性生长是基于血浆细胞抗原CD138和干细胞标志物乙醛脱氢酶的表达。实时定量聚合酶链式反应显示，短期处理MM CSC后，干细胞典型表达基因(Oct3/4、SOX2、NANOG和BMI1)的表达也降低。结论：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和独立的机制影响CSC。
Background: 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.Conclusions: 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.