mTOR Complex 1 Plays Critical Roles in Hematopoiesis and Pten-Loss-Evoked Leukemogenesis |
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Authors: | Kalaitzidis Demetrios Sykes Stephen M Wang Zhu Punt Natalie Tang Yuefeng Ragu Christine Sinha Amit U Lane Steven W Souza Amanda L Clish Clary B Anastasiou Dimitrios Gilliland D Gary Scadden David T Guertin David A Armstrong Scott A |
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Institution: | 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. |
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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. |
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