Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells
Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells
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DOI：
10.1038/nature04703
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发表时间：
2006-05-25
期刊：
影响因子：
64.8
通讯作者：
Morrison, Sean J.
中科院分区：
文献类型：
--
作者：
Yilmaz, Omer H.;Valdez, Riccardo;Morrison, Sean J.
最近的进展突出了正常干细胞和癌症干细胞之间广泛的表型和功能相似性。这就提出了一个问题，即是否可以开发出消除癌症干细胞而不消除正常干细胞的疾病疗法。在这里，我们解决这个问题，有条件地删除Pten肿瘤抑制基因在成人造血细胞。这导致骨髓增生性疾病在几天内和移植性白血病在几周内。Pten缺失也促进造血干细胞（HSC）增殖。然而，这通过细胞自主机制导致HSC耗竭，阻止这些细胞稳定重建辐射小鼠。与白血病起始细胞相反，HSC因此不能在没有Pten的情况下维持自身。这些作用主要由mTOR介导，因为它们被雷帕霉素抑制。雷帕霉素不仅耗尽了白血病起始细胞，而且恢复了正常的HSC功能。因此，可以靶向正常干细胞和癌症干细胞之间的机制差异，以在不损害正常干细胞的情况下耗尽癌症干细胞。
Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.