JCI：mTORC1能激活白血病干细胞的自我更新能力

在白血病中，癌症干细胞被认为是能增殖变成肿瘤细胞的。这些癌症干细胞的数量是很少的，其特性不同于其他肿瘤细胞包括抗常规药物治疗的能力增加。在白血病患者中，哺乳动物雷帕mTOR复合物1（mTORC1）形成包括mTOR和Raptor在内的多种蛋白质。虽然mTOR和Raptor消融后证实mTORC1是胚胎发育过程中正常细胞增殖和生存必不可少的因子，但mTORC1在癌症干细胞以及引发白血病中的目前还不清楚。
 
近日，日本金泽大学研究人员已经证明成年小鼠Raptor缺陷后，粒细胞和B细胞的发育受损，但不影响正常造血祖细胞的存活或增殖。此外在急性髓细胞性白血病模型中，Raptor导致mTORC1失活不影响癌症干细胞的自我更新能力，但会阻断其促发白血病的能力。 mTORC1的重新激活会恢复这些癌症干细胞促发白血病的能力。

他们的研究结果显示癌症干细胞的自我更新能力与其引发肿瘤的开始和传播的能力不同。

拓展阅读：

AI+mTOR抑制剂内分泌联合靶向治疗乳腺癌的又一尝试

mTOR信号抑制剂雷帕霉素及衍生物用于多囊肾的治疗

Nature：mTOR信号与癌症转移密切相关

Nature：揭示mTOR导致肿瘤转移机制和药物INK128作用机理

Cancer Cell：特异性抑制自噬治疗肾细胞癌

自噬与细胞代谢及疾病关系的研究进展

doi:10.1172/JCI62279
PMC:
PMID:

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.