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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Journal Article
Stem Cells,Cancer and Cancer Stem Cells
TL;DR: Research data show that more resistant stem cells than common cancer cells exist in cancer patients, and to identify unrecognized differences between cancer stem cells and cancer cells might be able to develop effective classification, diagnose and treat for cancer.
Journal ArticleDOI
Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy.
Yoshinobu Ichimura,Satoshi Waguri,Yu-shin Sou,Shun Kageyama,Jun Hasegawa,Ryosuke Ishimura,Tetsuya Saito,Yinjie Yang,Tsuguka Kouno,Toshiaki Fukutomi,Takayuki Hoshii,Atsushi Hirao,Kenji Takagi,Tsunehiro Mizushima,Hozumi Motohashi,Myung-Shik Lee,Tamotsu Yoshimori,Keiji Tanaka,Masayuki Yamamoto,Masaaki Komatsu +19 more
TL;DR: It is shown that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2, and that inhibitors of the interaction between phosphorylated p62 and Keap 1 have potential as therapeutic agents against human HCC.
Dissertation
Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy
Journal ArticleDOI
Autophagy in stem cells
Jun-Lin Guan,Anna Katharina Simon,Mark Prescott,Javier A. Menendez,Fei Liu,Fen Wang,Chenran Wang,Ernst J. Wolvetang,Alejandro Vazquez-Martin,Jue Zhang +9 more
TL;DR: A comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells is provided.
Journal ArticleDOI
Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia.
Lise Willems,Lise Willems,Nathalie Jacque,Arnaud Jacquel,Nathalie Neveux,Thiago Trovati Maciel,Mireille Lambert,Alain Schmitt,Laury Poulain,Alexa S. Green,Madalina Uzunov,Olivier Kosmider,Olivier Kosmider,Isabelle Radford-Weiss,Ivan C. Moura,Patrick Auberger,Norbert Ifrah,Valérie Bardet,Valérie Bardet,Nicolas Chapuis,Nicolas Chapuis,Catherine Lacombe,Catherine Lacombe,Patrick Mayeux,Patrick Mayeux,Jerome Tamburini,Jerome Tamburini,Didier Bouscary,Didier Bouscary +28 more
TL;DR: It is shown that glutamine removal inhibits mTORC1 and induces apoptosis in AML cells, and that l-ases upregulate glutamine synthase expression in leukemic cells and that a GS knockdown enhances l-ase-induced apoptotic response in someAML cells.
References
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Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies
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Dissertation
Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy
Journal ArticleDOI
AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias
Stephen M. Sykes,Steven W. Lane,Lars Bullinger,Demetrios Kalaitzidis,Rushdia Z. Yusuf,Borja Saez,Francesca Ferraro,Francois Mercier,Harshabad Singh,Kristina Brumme,Sanket S. Acharya,Claudia Scholl,Zuzana Tothova,Eyal C. Attar,Stefan Fröhling,Ronald A. DePinho,D. Gary Gilliland,Scott A. Armstrong,David T. Scadden +18 more
TL;DR: In this article, the authors show a converse role for AKT/FOXOs in acute myeloid leukemia (AML) and demonstrate that AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors.
Journal ArticleDOI
MOZ-TIF2, but Not BCR-ABL, Confers Properties of Leukemic Stem Cells to Committed Murine Hematopoietic Progenitors.
Brian J. P. Huntly,Hirokazu Shigematzu,Kenji Deguchi,Benjamin H. Lee,Shinichi Mizuno,Nicky Duclos,Rebecca Rowan,Sonia M Amaral,David P. Curley,Ifor R. Williams,Koichi Akashi,Gary Gilliland +11 more
TL;DR: In this article, the authors tested the ability of representative leukemia oncogenes to transform committed myeloid progenitor cells that lack the capacity for self-renewal, and showed that an active MOZ-TIF2, but not BCR-ABL, can collaborate with mutations induced by retroviral mutagenesis to confer properties of leukemic stem cells to committed progenitors.