title: mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis.
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.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Harvard Medical School and the Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Demetrios
authors.initials: D
authors.lastname: Kalaitzidis
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.forename: Natalie
authors.initials: N
authors.lastname: Punt
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Tang
authors.forename: Christine
authors.initials: C
authors.lastname: Ragu
authors.forename: Amit U
authors.initials: AU
authors.lastname: Sinha
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Souza
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Anastasiou
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: David A
authors.initials: DA
authors.lastname: Guertin
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse