mTOR Complex 1 Plays Critical Roles in Hematopoiesis and Pten-Loss-Evoked Leukemogenesis

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. º Homozygous deletion of Raptor reduces mTORC1 activity in HSPCs º Inactivation of mTORC1 leads to expansion of monocytes and pancytopenia º Raptor/mTORC1 activity is required for HSC regeneration º Raptor/mTORC1 is required for Pten-loss-evoked leukemogenesis mTOR signaling is associated with hematopoietic function and leukemogenesis, but how unique mTOR complexes contribute to pathogenesis is poorly understood. Deletion of Raptor and Rictor, scaffolding proteins defining mTORC1 and mTORC2, reveal that PTEN-driven leukemia requires mTORC1, findings that suggest that chronic mTORC1 inhibition can cause deleterious responses.