mTORC1 is essential for leukemia propagation but not stem cell self-renewal
Takayuki Hoshii,Yuko Tadokoro,Kazuhito Naka,Takako Ooshio,Teruyuki Muraguchi,Naoyuki Sugiyama,Tomoyoshi Soga,Kimi Araki,Ken Ichi Yamamura,Atsushi Hirao +9 more
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TLDR
Transplantation of Raptor-deficient undifferentiated AML cells in a limiting dilution revealed that mTORC1 is essential for leukemia initiation, and it was demonstrated that the reactivation of m TORC1 in those cells restored their leukemia-initiating capacity.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.read more
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Amino acid–insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells
Demetrios Kalaitzidis,Dongjun Lee,Alejo Efeyan,Youmna Kfoury,Naema Nayyar,David B. Sykes,Francois Mercier,Ani Papazian,Ninib Baryawno,Gabriel D. Victora,Donna Neuberg,David Alexander Sabatini,David T. Scadden +12 more
TL;DR: RagA is a molecular mechanism that distinguishes the functional attributes of reactive progenitors from a reserve stem cell pool and contributes to their molecular resilience to nutritional stress, a characteristic that is relevant to organismal viability in evolution and in modern HSC transplantation approaches.
Journal ArticleDOI
Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals
Daisuke Yamada,Takayuki Hoshii,Shingo Tanaka,Ahmed M. S. Hegazy,Masahiko Kobayashi,Yuko Tadokoro,Kumiko Ohta,Masaya Ueno,Mohamed A.E. Ali,Atsushi Hirao +9 more
TL;DR: Although mTORC1 hyperactivation itself may not be sufficient for gliomagenesis, it is a potent modifier of glioma development when combined with oncogenic signals.
Journal ArticleDOI
Rheb1-mTORC1 maintains macrophage differentiation and phagocytosis in mice.
Xiaomin Wang,Minghao Li,Yanan Gao,Juan Gao,Wan-Zhu Yang,Hao-Yue Liang,Qing Ji,Yanxin Li,Han-Zhi Liu,Jian Huang,Tao Cheng,Weiping Yuan +11 more
TL;DR: Rheb1 is critical for macrophage production and phagocytosis and executes these activities possibly via mTORC1-dependent pathway and is investigated using a Rheb 1 conditional deletion murine model.
Journal ArticleDOI
Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy
Magali Humbert,Magali Humbert,Kristina Seiler,Severin Mosimann,Vreni Rentsch,Katyayani Sharma,Katyayani Sharma,Amit V. Pandey,Amit V. Pandey,Sharon L. McKenna,Mario P. Tschan +10 more
TL;DR: In this article, the authors found that fat acid synthase (FASN) mRNA levels were significantly higher in acute myeloid leukemia (AML) patients than in healthy granulocytes or CD34+ hematopoietic progenitors, and that FASN reduction promoted translocation of transcription factor EB (TFEB) to the nucleus, paralleled by activation of CLEAR network genes and lysosomal biogenesis.
Posted ContentDOI
Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy
Magali Humbert,Kristina Seiler,Severin Mosimann,Vreni Rentsch,Sharon L. McKenna,Mario P. Tschan +5 more
TL;DR: The data demonstrate that inhibition of FASN expression in combination with ATRA treatment facilitates granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells.
References
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Journal ArticleDOI
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.
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TL;DR: It is shown that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolongedRapamycin treatment reduces the levels of m TORC2 below those needed to maintain Akt/PKB signaling.
Journal ArticleDOI
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
Kathryn E. O'Reilly,Fredi Rojo,Qing-Bai She,David B. Solit,Gordon B. Mills,Debra G. Smith,Heidi Lane,Francesco Hofmann,Daniel J. Hicklin,Dale L. Ludwig,José Baselga,Neal Rosen +11 more
TL;DR: The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation, and reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
Journal ArticleDOI
Molecular mechanisms of mTOR-mediated translational control
Xiaoju Max Ma,John Blenis +1 more
TL;DR: Recent findings on the regulators and effectors of mTOR are highlighted and specific cases that serve as paradigms for the different modes of m TOR regulation and its control of translation are discussed.