Barabé Frédéric, Kennedy James A, Hope Kristin J, Dick John E
Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
Science. 2007 Apr 27;316(5824):600-4. doi: 10.1126/science.1139851.
Our understanding of leukemia development and progression has been hampered by the lack of in vivo models in which disease is initiated from primary human hematopoietic cells. We showed that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells (L-ICs) that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The L-ICs retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. The properties of these cells provide a biological basis for several clinical hallmarks of MLL leukemias.
由于缺乏从原代人类造血细胞引发疾病的体内模型，我们对白血病发生和发展的理解受到了阻碍。我们发现，将表达混合谱系白血病（MLL）融合基因的原始人类造血细胞移植到免疫缺陷小鼠体内后，会产生髓系或淋巴系急性白血病，其特征与人类疾病相似。对连续移植小鼠的分析表明，该疾病由白血病起始细胞（L-ICs）维持，这些细胞随着时间的推移从具有种系免疫球蛋白重链（IgH）基因构型的原始细胞类型演变为含有重排IgH基因的细胞类型。L-ICs保留了髓系和淋巴系谱系潜能，并对微环境信号保持反应性。这些细胞的特性为MLL白血病的几个临床特征提供了生物学基础。
