Document Detail


mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis.
MedLine Citation:
PMID:  22958934     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mechanistic target of rapamycin (mTOR) pathway serves as a key sensor of cellular-energetic state and functions to maintain tissue homeostasis. Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) function and is associated with leukemogenesis. However, the roles of the unique mTOR complexes (mTORCs) in hematopoiesis and leukemogenesis have not been adequately elucidated. We deleted the mTORC1 component, regulatory-associated protein of mTOR (Raptor), in mouse HSCs and its loss causes a nonlethal phenotype characterized by pancytopenia, splenomegaly, and the accumulation of monocytoid cells. Furthermore, Raptor is required for HSC regeneration, and plays largely nonredundant roles with rapamycin-insensitive companion of mTOR (Rictor) in these processes. Ablation of Raptor also significantly extends survival of mice in models of leukemogenesis evoked by Pten deficiency. These data delineate critical roles for mTORC1 in hematopoietic function and leukemogenesis and inform clinical strategies based on chronic mTORC1 inhibition.
Authors:
Demetrios Kalaitzidis; Stephen M Sykes; Zhu Wang; Natalie Punt; Yuefeng Tang; Christine Ragu; Amit U Sinha; Steven W Lane; Amanda L Souza; Clary B Clish; Dimitrios Anastasiou; D Gary Gilliland; David T Scadden; David A Guertin; Scott A Armstrong
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell stem cell     Volume:  11     ISSN:  1875-9777     ISO Abbreviation:  Cell Stem Cell     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-10     Completed Date:  2013-05-29     Revised Date:  2014-07-08    
Medline Journal Info:
Nlm Unique ID:  101311472     Medline TA:  Cell Stem Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  429-39     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE32265
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins
Cell Cycle / genetics
Cell Differentiation
Cell Lineage
Cell Transformation, Neoplastic / pathology*
Disease Models, Animal
Gene Expression Regulation, Leukemic
Hematopoiesis* / genetics
Hematopoietic Stem Cell Mobilization
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / metabolism,  pathology
Homeostasis
Leukemia / enzymology*,  pathology*
Mice
Multiprotein Complexes / metabolism*
PTEN Phosphohydrolase / deficiency*,  metabolism
Survival Analysis
TOR Serine-Threonine Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
CA105423/CA/NCI NIH HHS; CA66996/CA/NCI NIH HHS; DK049216/DK/NIDDK NIH HHS; DK050234/DK/NIDDK NIH HHS; HL097748/HL/NHLBI NIH HHS; HL097794/HL/NHLBI NIH HHS; HL100402/HL/NHLBI NIH HHS; K01 DK092300/DK/NIDDK NIH HHS; K01DK092300/DK/NIDDK NIH HHS; K99 CA158461/CA/NCI NIH HHS; R00 CA129613/CA/NCI NIH HHS; R01 DK050234/DK/NIDDK NIH HHS; R01 HL044851/HL/NHLBI NIH HHS; R01 HL097794/HL/NHLBI NIH HHS; U01 HL100402/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Carrier Proteins; 0/Multiprotein Complexes; 0/Rptor protein, mouse; 0/mechanistic target of rapamycin complex 1; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections
Comment In:
Cell Stem Cell. 2012 Sep 7;11(3):281-2   [PMID:  22958924 ]

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