Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia
Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia
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DOI：
10.1016/j.ccr.2008.04.020
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发表时间：
2008-06-01
期刊：
影响因子：
50.3
通讯作者：
Mulloy, James C.
中科院分区：
文献类型：
--
作者：
Wei, Junping;Wunderlich, Mark;Mulloy, James C.
在小鼠细胞中建立混合系白血病的可靠模型一直很难实现。我们发现MLL-AF 9在人CD 34+细胞中的表达诱导免疫缺陷小鼠的急性髓系、淋巴系或混合系白血病。一些白血病干细胞（LSC）是多能的，可以通过改变生长因子或受体小鼠品系来定向谱系，突出了微环境线索的重要性。其他LSC是严格的谱系定向，证明了MLL疾病中干细胞区室的异质性。通过药理学或遗传学手段靶向Rac信号通路导致MLL-AF 9细胞的快速和特异性凋亡，表明Rac信号通路可能是ML重排AML的有效治疗靶点。
Faithful modeling of mixed-lineage leukemia in murine cells has been difficult to achieve. We show that expression of MLL-AF9 in human CD34+ cells induces acute myeloid, lymphoid, or mixed-lineage leukemia in immunodeficient mice. Some leukemia stem cells (LSC) were multipotent and could be lineage directed by altering either the growth factors or the recipient strain of mouse, highlighting the importance of microenvironmental cues. Other LSC were strictly lineage committed, demonstrating the heterogeneity of the stem cell compartment in MLL disease. Targeting the Rac signaling pathway by pharmacologic or genetic means resulted in rapid and specific apoptosis of MLL-AF9 cells, suggesting that the Rac signaling pathway may be a valid therapeutic target in MLL-rearranged AML.