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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Lysosomes and Their Role in Regulating the Metabolism of Hematopoietic Stem Cells
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Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia
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A gain‐of‐function mutation in microRNA 142 is sufficient to cause the development of T‐cell leukemia in mice
Shingo Kawano,Kimi Araki,Jie Bai,Imari Furukawa,Keigo Tateishi,Kumiko Yoshinobu,Shingo Usuki,Rachael Nimmo,Tadashi Kaname,M. Yoshihara,Satoru Takahashi,Goro Sashida,Masatake Araki +12 more
TL;DR: In this paper , the role of miR•142 mutation in blood cancers was investigated using the CRISPR-Cas9 system, which was used to generate miR−142−55A>G mutant knock-in mice, simulating the most frequent mutation in patients with miR´142 mutated AML/MDS.
treating acute myeloid leukemia Inhibiting glutamine uptake represents an attractive new strategy for
Catherine Lacombe,Patrick Mayeux,Jerome Tamburini,Didier Bouscary Radford-Weiss,Ivan Moura,Patrick Auberger,Norbert Ifrah,Valérie Bardet,Nicolas Chapuis,Alain Schmitt,Laury Poulain,Alexa S. Green,Madalina Uzunov,Olivier Kosmider,Nathalie Jacque,Arnaud Jacquel,Nathalie Neveux,Thiago Trovati Maciel +17 more
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RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia.
Pham Thi Xuan Loc,Huiyun Peng,Masaya Ueno,Susumu Kohno,Atuso Kasada,Kazuyoshi Hosomichi,Takehiro Sato,Kenta Kurayoshi,Masahiko Kobayashi,Yuko Tadokoro,Atsuko Kasahara,Mahmoud I. Shoulkamy,Bo Xiao,Paul F. Worley,Chiaki Takahashi,Atsushi Tajima,Atsushi Hirao +16 more
TL;DR: In this paper , the authors reported that Ras homolog enriched in brain (RHEB), a critical regulator of mTOR complex 1 activity, is a potential target for T-ALL therapy and established an sgRNA library that comprehensively targeted mTOR upstream and downstream pathways, including autophagy.
References
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Journal ArticleDOI
Stem cells, cancer, and cancer stem cells
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Journal ArticleDOI
mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery
Do Hyung Kim,Dos D. Sarbassov,Siraj M. Ali,Jessie E. King,Robert R. Latek,Hediye Erdjument-Bromage,Paul Tempst,David M. Sabatini +7 more
TL;DR: It is reported that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.
Journal ArticleDOI
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.
Dos D. Sarbassov,Siraj M. Ali,Siraj M. Ali,Shomit Sengupta,Shomit Sengupta,Joon Ho Sheen,Joon Ho Sheen,Peggy P. Hsu,Peggy P. Hsu,Alex F. Bagley,Alex F. Bagley,Andrew L. Markhard,Andrew L. Markhard,David M. Sabatini,David M. Sabatini +14 more
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.