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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

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 8

mTORC1-independent long-term survival of AML cells in vivo.

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mTORC1-independent long-term survival of AML cells in vivo.
(A) Presence...
(A) Presence of AML cells surviving long-term in BM. 10–400 K+G– cells from Raptorfl/flCreER+TAM AML mice were transplanted into recipients, and GFP expression was evaluated in BM-MNCs 100 days after transplantation. Data shown are the percentages of GFP+ cells among total BM-MNCs. Horizontal lines are the mean percentages of GFP+ cells in cases where GFP+ cells were present. Numbers of mice possessing GFP+ cells/total number of recipients are shown at the bottom of the panel. (B) Morphological analysis of RaptorΔ/Δ AML cells. GFP– and GFP+ cells were isolated from BM-MNCs of recipients possessing GFP+ cells. Cells were stained with May-Grünwald/Giemsa. Scale bars: 50 μm. (C) Flow cytometric characterization of the AML cells in A. Results of two representative analyses are shown. (D) Phosphorylation of mTOR signaling pathway proteins in RaptorΔ/Δ (long-term Raptor-deficient) AML cells. Immunoblotting to detect the indicated proteins was performed on lysates of GFP+ K+G– cells isolated from the following mice: lanes 1 and 6, Raptorfl/flCreER–TAM AML (fl/fl; TAM–, control); lane 2, Raptorfl/flCreER+TAM AML at 14 days post-TAM (fl/fl; TAM+); lanes 3–5, RaptorΔ/Δ AML (Δ/Δ). (E and F) Analysis of apoptosis and cell cycle in RaptorΔ/Δ AML cells. The apoptosis rate (E) and proportion of cells in the cell cycle (F) of the indicated subpopulations from Raptorfl/flCreER–TAM AML cells (fl/fl; TAM–, control) and RaptorΔ/Δ AML cells (Δ/Δ) were evaluated by using Annexin V/7AAD staining and BrdU incorporation, respectively. Data shown in E and F are the mean ± SD of Annexin V+7AAD– cells (n = 4) and BrdU+ cells (n = 4), respectively. **P < 0.01 (Student’s t test).

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