mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion.
mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion.
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DOI：
10.1016/j.stem.2010.09.015
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发表时间：
2010-11-05
期刊：
影响因子：
23.9
通讯作者：
Morrison, Sean J.
中科院分区：
文献类型：
--
作者：
Lee, Jae Y.;Nakada, Daisuke;Yilmaz, Omer H.;Tothova, Zuzana;Joseph, Nancy M.;Lim, Megan S.;Gilliland, D. Gary;Morrison, Sean J.
Pten缺乏会耗尽造血干细胞（HSC），但会扩增白血病起始细胞，而mTOR抑制剂雷帕霉素会阻断这些作用。了解mTOR激活对HSC与白血病起始细胞的相反作用可以改善抗白血病治疗。我们发现Pten缺陷的HSC的耗竭不是由氧化应激引起的，并且不能被N-乙酰半胱氨酸阻断。相反，Pten缺失诱导和雷帕霉素减弱了HSC中p16 Ink 4a和p53的表达，以及其他造血细胞中p19 Arf和p53的表达。Pten缺失后p53抑制白血病发生并促进HSC耗竭。p16 Ink 4a也促进HSC耗竭，但抑制白血病发生的作用有限。p19 Arf强烈抑制白血病发生，但不消耗HSC。次级突变减弱了Pten缺失后出现的某些白血病的肿瘤抑制反应。因此，mTOR激活通过肿瘤抑制反应耗尽HSC，该肿瘤抑制反应通过致白血病克隆中的二次突变而减弱。
Pten deficiency depletes hematopoietic stem cells (HSCs) but expands leukemia-initiating cells and the mTOR inhibitor, rapamycin, blocks these effects. Understanding the opposite effects of mTOR activation on HSCs versus leukemia-initiating cells could improve anti-leukemia therapies. We found that the depletion of Pten-deficient HSCs was not caused by oxidative stress and could not be blocked by N-acetyl-cysteine. Instead, Pten deletion induced, and rapamycin attenuated, the expression of p16Ink4a and p53 in HSCs, and p19Arf and p53 in other hematopoietic cells. p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16Ink4a also promoted HSC depletion but had a limited role suppressing leukemogenesis. p19Arf strongly suppressed leukemogenesis but did not deplete HSCs. Secondary mutations attenuated this tumor suppressor response in some leukemias that arose after Pten deletion. mTOR activation therefore depletes HSCs by a tumor suppressor response that is attenuated by secondary mutations in leukemogenic clones.
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2008-09-29
期刊：
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