Matsui William, Wang Qiuju, Barber James P, Brennan Sarah, Smith B Douglas, Borrello Ivan, McNiece Ian, Lin Lan, Ambinder Richard F, Peacock Craig, Watkins D Neil, Huff Carol Ann, Jones Richard J
The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Cancer Res. 2008 Jan 1;68(1):190-7. doi: 10.1158/0008-5472.CAN-07-3096.
Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138(+) multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138(neg) B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138(+) multiple myeloma plasma cells but had little effect on CD138(neg) precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138(neg) cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury.
许多药物对多发性骨髓瘤有效，但大多数患者会复发。这种临床模式表明，大多数癌细胞被清除，但具有介导肿瘤再生的克隆形成潜力的细胞对化疗相对耐药。我们之前的数据表明，CD138(+)多发性骨髓瘤浆细胞不能长期增殖，而是起源于具有克隆形成能力的CD138(-)B细胞。我们比较了这些不同细胞类型对临床抗骨髓瘤药物的相对敏感性，发现地塞米松、来那度胺、硼替佐米和4-羟基环磷酰胺在体外可抑制CD138(+)多发性骨髓瘤浆细胞，但对CD138(-)前体细胞影响不大。我们进一步对具有克隆形成能力的多发性骨髓瘤细胞进行了表征，并使用Hoechst侧群和醛脱氢酶检测法对细胞系进行了染色。每种检测方法都鉴定出了CD138(-)细胞，表明它们具有高药物外排能力和细胞内药物解毒活性。我们还发现，表达记忆B细胞标志物CD20和CD27的多发性骨髓瘤细胞在体外可产生具有克隆形成能力的多发性骨髓瘤生长，并且在初次和二次移植期间均可植入免疫缺陷的非肥胖糖尿病/严重联合免疫缺陷小鼠体内。此外，侧群和醛脱氢酶检测法均能够鉴定多发性骨髓瘤患者外周血中的循环克隆型记忆B细胞群体。我们的结果表明，循环克隆型B细胞群体代表多发性骨髓瘤干细胞，这些细胞的相对耐药性是由保护正常干细胞免受毒性损伤的过程介导的。
