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mTORC1 is essential for leukemia propagation but not stem cell self-renewal
Takayuki Hoshii, … , Ken-ichi Yamamura, Atsushi Hirao
Takayuki Hoshii, … , Ken-ichi Yamamura, Atsushi Hirao
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):2114-2129. https://doi.org/10.1172/JCI62279.
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Research Article Article has an altmetric score of 6

mTORC1 is essential for leukemia propagation but not stem cell self-renewal

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Abstract

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.

Authors

Takayuki Hoshii, Yuko Tadokoro, Kazuhito Naka, Takako Ooshio, Teruyuki Muraguchi, Naoyuki Sugiyama, Tomoyoshi Soga, Kimi Araki, Ken-ichi Yamamura, Atsushi Hirao

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Figure 7

Raptor-deficient AML stem cells show defective leukemia-initiating capacity.

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Raptor-deficient AML stem cells show defective leukemia-initiating capa...
(A) Limiting dilution transplantation assay. The indicated numbers of K+G– AML cells from the mice 14 days after control or TAM treatment were transplanted into lethally irradiated recipients along with WT BM-MNCs (rescue cells), and survival was monitored (n = 5/group). *P < 0.05, **P < 0.01 (log-rank test). (B) Colony-forming ability of AML cells. K–G+ and K+G– AML cells were isolated from Raptorfl/flCreER AML mice 14 days after control or TAM treatment and cultured in semisolid medium for 7 days. Data are the mean colony numbers ± SD (n = 3). (C) Apoptosis of K+G– AML cells after 12 hours of stimulation with the cytokines SCF, IL-3, and IL-6. Data shown are the mean percentage ± SD of Annexin V+7AAD– cells (n = 8). (D) Cell cycle of K+G– AML cells after 12 hours of stimulation with the same set of cytokines. Data shown are the mean percentage ± SD of BrdU+ cells (n = 8). (E) Expression level of c-Kit on K+G– AML cells after 12 hours of cytokine stimulation. Representative histograms are shown in the left panel. Shaded histogram: nonstained AML cells; dotted line: Raptorfl/flCreER–TAM AML cells; solid line: Raptorfl/flCreER+TAM AML cells. Data in the right panel are the mean percentage ± SD of MFI of c-Kit (n = 3). For B–E, **P < 0.01 (Student’s t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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