Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Science. 2010 Mar 26;327(5973):1650-3. doi: 10.1126/science.1186624.
Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/beta-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/beta-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. beta-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in AML.
白血病干细胞（LSCs）具有无限自我更新的能力，是白血病维持的根源。由于选择性清除 LSCs 可能带来实质性的治疗益处，因此人们对鉴定控制其发育的信号通路产生了浓厚的兴趣。我们在由 Hoxa9 和 Meis1a 癌基因共表达或融合癌蛋白 MLL-AF9 诱导的急性髓系白血病（AML）小鼠模型中研究了 LSCs。我们表明，Wnt/β-连环蛋白信号通路对于源自造血干细胞（HSC）或更分化的粒细胞-巨噬细胞祖细胞（GMP）的 LSCs 的自我更新是必需的。由于 Wnt/β-连环蛋白途径在 HSCs 中通常活跃而在 GMP 中不活跃，这些结果表明，某些癌基因诱导祖细胞转化需要重新激活β-连环蛋白信号。β-连环蛋白对于成体 HSCs 的自我更新不是绝对必需的；因此，靶向 Wnt/β-连环蛋白途径可能是 AML 的新治疗机会。
