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Cell Stem Cell DOI:10.1016/j.stem.2012.06.009

mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis.

Publication TypeJournal Article
Year of Publication2012
AuthorsKalaitzidis, D, Sykes, SM, Wang, Z, Punt, N, Tang, Y, Ragu, C, Sinha, AU, Lane, SW, Souza, AL, Clish, CB, Anastasiou, D, D Gilliland, G, Scadden, DT, Guertin, DA, Armstrong, SA
JournalCell Stem Cell
Volume11
Issue3
Pages429-39
Date Published2012 Sep 07
ISSN1875-9777
KeywordsAdaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Cycle, Cell Differentiation, Cell Lineage, Cell Transformation, Neoplastic, Disease Models, Animal, Gene Expression Regulation, Leukemic, Hematopoiesis, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Homeostasis, Leukemia, Mice, Multiprotein Complexes, PTEN Phosphohydrolase, Survival Analysis, TOR Serine-Threonine Kinases
Abstract

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.

DOI10.1016/j.stem.2012.06.009
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22958934?dopt=Abstract

Alternate JournalCell Stem Cell
PubMed ID22958934
PubMed Central IDPMC3743253
Grant ListCA66996 / CA / NCI NIH HHS / United States
R00 CA158461 / CA / NCI NIH HHS / United States
DK049216 / DK / NIDDK NIH HHS / United States
U01 CA105423 / CA / NCI NIH HHS / United States
R01 HL044851 / HL / NHLBI NIH HHS / United States
K01DK092300 / DK / NIDDK NIH HHS / United States
HL097748 / HL / NHLBI NIH HHS / United States
HL100402 / HL / NHLBI NIH HHS / United States
CA105423 / CA / NCI NIH HHS / United States
K99 CA158461 / CA / NCI NIH HHS / United States
R00 CA129613 / CA / NCI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
U01 HL100402 / HL / NHLBI NIH HHS / United States
HL097794 / HL / NHLBI NIH HHS / United States
K01 DK092300 / DK / NIDDK NIH HHS / United States
R01 HL097794 / HL / NHLBI NIH HHS / United States
R01 HL097748 / HL / NHLBI NIH HHS / United States
R01 DK050234 / DK / NIDDK NIH HHS / United States
DK050234 / DK / NIDDK NIH HHS / United States