Jin Liqing, Hope Kristin J, Zhai Qiongli, Smadja-Joffe Florence, Dick John E
Division of Cell and Molecular Biology, University Health Network Suite 8-355, Toronto Medical Discovery Tower, 101 College Street, Toronto, M5G 1L7, Canada.
Nat Med. 2006 Oct;12(10):1167-74. doi: 10.1038/nm1483. Epub 2006 Sep 24.
The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.
急性髓系白血病（AML）患者的长期生存率极低。AML的永久治愈需要清除白血病干细胞（LSCs），这是唯一能够启动和维持白血病克隆层次结构的细胞类型。我们报告了一种使用针对黏附分子CD44的激活单克隆抗体的治疗方法。将这种抗体体内给予移植了人类AML的非肥胖糖尿病-严重联合免疫缺陷小鼠，可显著减少白血病细胞的再增殖。连续移植小鼠中无白血病表明AML LSCs是直接靶点。这种根除的潜在机制包括干扰向干细胞支持性微环境龛的转运以及改变AML-LSC的命运，从而确定CD44是AML LSCs的关键调节因子。AML LSCs需要与龛相互作用以维持其干细胞特性这一发现提供了一种消除静止AML LSCs的治疗策略，并且可能适用于其他类型的癌症干细胞。
