mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells
mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells
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DOI：
10.1186/1476-4598-9-292
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发表时间：
2010-11-10
期刊：
影响因子：
37.3
通讯作者：
Rassidakis, George Z.
中科院分区：
文献类型：
--
作者：
Chen, Weina;Drakos, Elias;Rassidakis, George Z.
FLT 3基因的激活突变至少部分通过PI 3 K/AKT的激活介导白血病发生。已知哺乳动物雷帕霉素靶蛋白（mTOR）-Raptor信号传导途径作用于AKT下游。在这里，我们表明，mTOR效应器，4 EBP 1，p70 S6 K和rpS 6，在培养的和原代FLT 3突变的急性髓性白血病（AML）细胞中高度活化。引入表达组成型激活的FLT 3激酶的FLT 3-ITD进一步激活BaF 3细胞中的mTOR及其下游效应物。我们还发现mTOR信号传导有助于肿瘤细胞存活，如通过PI 3 K/AKT/mTOR的药理学抑制或mTOR基因的完全沉默所证明的。此外，FLT 3激酶的抑制导致与FLT 3突变的AML细胞的存活率降低相关的mTOR信号转导的下调。这些发现表明，mTOR信号传导在活化的FLT 3激酶的下游起作用，从而有助于肿瘤细胞存活，并且可能代表具有突变的FLT 3的AML患者的有希望的治疗靶点。
Activating mutations of the FLT3 gene mediate leukemogenesis, at least in part, through activation of PI3K/AKT. The mammalian target of rapamycin (mTOR)-Raptor signaling pathway is known to act downstream of AKT. Here we show that the mTOR effectors, 4EBP1, p70S6K and rpS6, are highly activated in cultured and primary FLT3-mutated acute myeloid leukemia (AML) cells. Introduction of FLT3-ITD expressing constitutively activated FLT3 kinase further activates mTOR and its downstream effectors in BaF3 cells. We also found that mTOR signaling contributes to tumor cell survival, as demonstrated by pharmacologic inhibition of PI3K/AKT/mTOR, or total silencing of the mTOR gene. Furthermore, inhibition of FLT3 kinase results in downregulation of mTOR signaling associated with decreased survival of FLT3-mutated AML cells. These findings suggest that mTOR signaling operates downstream of activated FLT3 kinase thus contributing to tumor cell survival, and may represent a promising therapeutic target for AML patients with mutated-FLT3.