Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9
Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9
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DOI：
10.1038/nature04980
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发表时间：
2006-08-17
期刊：
影响因子：
64.8
通讯作者：
Armstrong, Scott A.
中科院分区：
文献类型：
--
作者：
Krivtsov, Andrei V.;Twomey, David;Armstrong, Scott A.
白血病和其他癌症具有罕见的细胞群，能够无限自我更新，这是癌症发生和维持所必需的（1-7）。这些癌症干细胞的根除可能是任何成功的抗癌治疗的关键部分，并且可以解释为什么传统的癌症治疗通常在减少肿瘤负担方面有效，但很少治愈。鉴于正常和癌症干细胞都能够自我更新，如果要开发靶向治疗，癌症干细胞与正常组织干细胞相似的程度是一个关键问题。然而，目前尚不清楚癌症干细胞是否必须与正常组织干细胞表型相似，或者它们是否可以保留定向祖细胞的身份。在这里，我们表明，白血病干细胞（LSC）可以保持其起源的祖细胞的全球身份，同时激活有限的干细胞或自我更新相关程序。我们通过引入由t（9; 11）（p22; q23）编码的MLL-AF 9融合蛋白从定向粒细胞巨噬细胞祖细胞中起始的白血病中分离LSC。当仅转移4个细胞时，LSC能够将白血病转移至第二受体小鼠，并且具有与正常粒细胞巨噬细胞祖细胞非常相似的免疫表型和全局基因表达谱。然而，在正常造血干细胞中高度表达的一组基因在LSC中被重新激活。因此，LSC可以从定向祖细胞产生，而无需广泛的基因表达重编程，并且在该过程中激活了白血病自我更新相关的签名。我们的研究结果定义了从正常祖细胞到癌症干细胞的进展，并表明靶向在异常环境中表达的自我更新程序是可能的。
Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance(1-7). Eradication of these cancer stem cells is probably a critical part of any successful anti-cancer therapy, and may explain why conventional cancer therapies are often effective in reducing tumour burden, but are only rarely curative. Given that both normal and cancer stem cells are capable of self-renewal, the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. However, it remains unclear whether cancer stem cells must be phenotypically similar to normal tissue stem cells or whether they can retain the identity of committed progenitors. Here we show that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme. We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL - AF9 fusion protein encoded by the t(9; 11)(p22; q23). The LSC were capable of transferring leukaemia to secondary recipient mice when only four cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal haematopoietic stem cells was re-activated in LSC. LSC can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukaemia self-renewal-associated signature is activated in the process. Our findings define progression from normal progenitor to cancer stem cell, and suggest that targeting a self-renewal programme expressed in an abnormal context may be possible.