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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 1

Conditional deletion of Raptor causes abnormalities in the hematopoietic organs of adult mice.

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Conditional deletion of Raptor causes abnormalities in the hematopoietic...
(A) Targeting strategy to create the floxed Raptor (Raptorfl) allele. The targeting vector includes a FRT-flanked neo cassette (PGK promoter–driven neomycin resistance gene) for positive selection and a diphtheria toxin A (DTA) gene for negative selection. Raptor exon 2 is flanked by loxP sites. The neo cassette of the Raptorfl;neo allele was removed by crossing Raptorfl;neo mice with CAG-FLP mice. Exon 2 was removed by Cre recombinase to give the RaptorΔ allele. Probes for Southern blotting (5ι probe, Neo) and primers for PCR (a, b, c) are indicated. E, EcoRI; S, SacI. (B) Body weight of Raptorfl/fl+TAM (control) and Raptorfl/flCreER+TAM (Raptor-deficient) mice. Data shown are the mean body weight ± SD (n = 5). (C) Survival of control and Raptor-deficient mice. P = 0.0003 (log-rank test; n = 15). (D) Decreased numbers of BM-MNCs. Data shown are the mean BM-MNC number ± SD in hind legs of control and Raptor-deficient mice at 10 days post-TAM (n = 12). (E) Organ weights of control and Raptor-deficient mice at 10 days post-TAM. Data shown are the mean relative organ weight (% of total body weight) ± SD (n = 5). *P < 0.05, **P < 0.01 (Student’s t test).

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