Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression.
Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression.
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DOI：
10.1016/j.stem.2012.05.026
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发表时间：
2012-09-07
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：
Magee, Jeffrey A.;Ikenoue, Tsuneo;Nakada, Daisuke;Lee, Jae Y.;Guan, Kun-Liang;Morrison, Sean J.
成年小鼠造血细胞中Pten缺失激活PI 3-激酶途径，诱导造血干细胞（HSC）增殖、HSC耗竭和白血病发生。Pten在人类白血病中也会发生突变，但在儿童早期白血病中很少发生突变。我们推测这反映了PI 3-激酶通路调节的发育变化。在这里，我们表明，Rictor删除防止白血病和HSC耗尽后，在成年小鼠Pten删除，牵连mTORC 2激活在这些过程中。然而，Rictor基因缺失对正常HSC的功能影响不大。此外，Pten从新生儿HSC的缺失没有激活PI 3-激酶途径或促进HSC增殖，HSC消耗或白血病发生。因此，Pten在成人而非新生儿HSC中是负调节mTORC 2信号传导所必需的。这表明新生细胞不需要成体细胞中的一些关键肿瘤抑制机制。因此，关键信号通路的发育变化赋予干细胞自我更新和肿瘤抑制机制的时间变化。
Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.
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影响因子：
3.7
作者：
Karrman, Kristina;Forestier, Erik;Johansson, Bertil
通讯作者：
Johansson, Bertil
影响因子：
3.5
作者：
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影响因子：
64.5
作者：
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通讯作者：
Morrison, SJ
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Zheng P
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH