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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 9

Restoration of leukemia-initiating capacity of long-term Raptor-deficient AML stem cells by mTORC1 reactivation.

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Restoration of leukemia-initiating capacity of long-term Raptor-deficien...
(A–C) Leukemia development upon restoration of Raptor. Recipient mice were transplanted with BM-MNCs (including RaptorΔ/Δ AML cells) infected with either control retrovirus expressing KO alone or retrovirus expressing hRAPTOR (hRAPTOR/KO). Survival (A), total number of wbc in PB (B), and the mean percentage ± SD of GFP+ cells in PB (C) of these recipients were analyzed 26–35 days after transplantation. For A, the P value was determined by the log-rank test. (D) Flow cytometric analysis of RaptorΔ/Δ+hRAPTOR/KO AML cells. Representative data for GFP/KO fluorescence (left) and c-Kit/Gr-1 expression (right) of BM-MNCs from the recipient mice in A–C are shown. Values are the mean percentage ± SD of the indicated subpopulations (n = 7). (E) Phosphorylation of mTOR signaling pathway proteins in RaptorΔ/Δ+hRAPTOR/KO AML cells. Immunoblotting to detect the indicated proteins was performed on lysates of the indicated AML cell subpopulations prepared from the following mice: lane 1, Raptorfl/flCreER–TAM (TAM-, control); lane 2, RaptorΔ/Δ; lanes 3–5, RaptorΔ/Δ+hRAPTOR/KO (case 1); lanes 6–8, RaptorΔ/Δ+hRAPTOR/KO (case 2). (F) Colony-forming ability of RaptorΔ/Δ+hRAPTOR/KO AML cells. K+G– or K–G+ (GFP+KO+) subpopulations isolated from among RaptorΔ/Δ+hRAPTOR/KO AML cells were cultured in semisolid medium for 7 days. Data are the mean colony number ± SD (n = 3). (G) The survival of recipient mice transplanted with 100 K+G–RaptorΔ/Δ+hRAPTOR/KO AML cells was monitored (n = 23). (H) Model of the role of mTORC1 in AML stem cell regulation. See text for explanation. **P < 0.01 (Student’s t test).

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