在白血病中，癌癥干細(xì)胞被認(rèn)為是能增殖變成腫瘤細(xì)胞的,。這些癌癥干細(xì)胞的數(shù)量是很少的,，其特性不同于其他腫瘤細(xì)胞包括抗常規(guī)藥物治療的能力增加。在白血病患者中,，哺乳動物雷帕mTOR復(fù)合物1（mTORC1）形成包括mTOR和Raptor在內(nèi)的多種蛋白質(zhì),。雖然mTOR和Raptor消融后證實mTORC1是胚胎發(fā)育過程中正常細(xì)胞增殖和生存必不可少的因子，但mTORC1在癌癥干細(xì)胞以及引發(fā)白血病中的目前還不清楚,。
近日,，日本金澤大學(xué)研究人員已經(jīng)證明成年小鼠Raptor缺陷后，粒細(xì)胞和B細(xì)胞的發(fā)育受損,，但不影響正常造血祖細(xì)胞的存活或增殖,。此外在急性髓細(xì)胞性白血病模型中，Raptor導(dǎo)致mTORC1失活不影響癌癥干細(xì)胞的自我更新能力,，但會阻斷其促發(fā)白血病的能力,。 mTORC1的重新激活會恢復(fù)這些癌癥干細(xì)胞促發(fā)白血病的能力。
他們的研究結(jié)果顯示癌癥干細(xì)胞的自我更新能力與其引發(fā)腫瘤的開始和傳播的能力不同,。（生物谷：Bioon.com)
doi:10.1172/JCI62279
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mTORC1 is essential for leukemia propagation but not stem cell self-renewal
Takayuki Hoshii, Yuko Tadokoro, Kazuhito Naka, Takako Ooshio, Teruyuki Muraguchi, Naoyuki Sugiyama, Tomoyoshi Soga, Kimi Araki, Ken-ichi Yamamura and Atsushi Hirao
Although dysregulation of mTOR complex 1 (mTORC1) promotes leukemogenesis, how mTORC1 affects established leukemia is unclear. We investigated the role of mTORC1 in mouse hematopoiesis using a mouse model of conditional deletion of Raptor, an essential component of mTORC1. Raptor deficiency impaired granulocyte and B cell development but did not alter survival or proliferation of hematopoietic progenitor cells. In a mouse model of acute myeloid leukemia (AML), Raptor deficiency significantly suppressed leukemia progression by causing apoptosis of differentiated, but not undifferentiated, leukemia cells. mTORC1 did not control cell cycle or cell growth in undifferentiated AML cells in vivo. Transplantation of Raptor-deficient undifferentiated AML cells in a limiting dilution revealed that mTORC1 is essential for leukemia initiation. Strikingly, a subset of AML cells with undifferentiated phenotypes survived long-term in the absence of mTORC1 activity. We further demonstrated that the reactivation of mTORC1 in those cells restored their leukemia-initiating capacity. Thus, AML cells lacking mTORC1 activity can self-renew as AML stem cells. Our findings provide mechanistic insight into how residual tumor cells circumvent anticancer therapies and drive tumor recurrence.
