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

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 2

Deletion of Raptor impairs granulocyte and B cell development but does not alter progenitor cell survival or proliferation.

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Deletion of Raptor impairs granulocyte and B cell development but does n...
(A) Flow cytometric analysis of BM-MNCs from control and Raptor-deficient mice. Images represent data for HSCs/MPPs (K+S+L–), CMPs (Lin–c-Kit+Sca-1–FcgRIII/II–CD34+), GMPs (Lin–c-Kit+Sca-1–FcgRIII/II+CD34+), MEPs (Lin-c-Kit+Sca-1–FcgRIII/II–CD34–), CLPs (IL-7Rα+Lin-c-KitmidSca-1mid), myeloid lineage cells (Mac-1/Gr-1), and B lineage cells (B220/IgM). Values are the mean percentage ± SD of the specified subpopulation among total BM-MNCs (n = 4). (B) Apoptosis. BM-MNCs from control and Raptor-deficient mice were subjected to TUNEL staining, and the indicated subpopulations were analyzed by flow cytometry. Data shown are the mean ± SD of TUNEL+ cells (n = 3). (C) Cell cycle. BrdU was injected i.p. into mice 2 hours prior to sacrifice. The indicated BM cell populations were stained with an anti-BrdU Ab and analyzed by flow cytometry. Data are the mean percentage ± SD of BrdU+ cells (n = 3). (D and E) Colony-forming ability. K+S+L– cells (D) and GMP cells (E) were isolated from BM-MNCs of control and Raptor-deficient mice and cultured for 10 days in semisolid medium. Data are the mean colony number ± SD (n = 3). Colony diameters are indicated. (F) Flow cytometric analysis of the differentiation into myeloid and B lineage cells of control and Raptor-deficient K+S+L– cells cultured on stromal cells. Raptorfl/fl or Raptorfl/flCreER K+S+L– cells were cultured on a layer of OP-9 stromal cells for 2 weeks in the presence or absence of TAM. Data shown are the percentage ± SD of B220+ Mac-1+ cells among CD45+-gated cells (n = 3). One flow cytometric analysis representative of 3 independent experiments is shown. *P < 0.05, **P < 0.01 (Student’s t test).