title: Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis.
abstract: mTOR integrates signals from nutrients and growth factors to control protein synthesis, cell growth, and survival. Although mTOR has been established as a therapeutic target in hematologic malignancies, its physiological role in regulating hematopoiesis remains unclear. Here we show that conditional gene targeting of mTOR causes bone marrow failure and defects in multi-lineage hematopoiesis including myelopoiesis, erythropoiesis, thrombopoiesis, and lymphopoiesis. mTOR deficiency results in loss of quiescence of hematopoietic stem cells, leading to a transient increase but long-term exhaustion and defective engraftment of hematopoietic stem cells in lethally irradiated recipient mice. Furthermore, ablation of mTOR causes increased apoptosis in lineage-committed blood cells but not hematopoietic stem cells, indicating a differentiation stage-specific function. These results demonstrate that mTOR is essential for hematopoietic stem cell engraftment and multi-lineage hematopoiesis.
authors.affiliation: Department of Biotechnology, Jinan University, Guangzhou, Guangdong, China. yi.zheng@cchmc.org
authors.forename: Fukun
authors.initials: F
authors.lastname: Guo
authors.forename: Shuangmin
authors.initials: S
authors.lastname: Zhang
authors.forename: Matthew
authors.initials: M
authors.lastname: Grogg
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Varney
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Jun-Qi
authors.initials: JQ
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Sara
authors.initials: S
authors.lastname: Kozma
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018390:Gene Targeting / Q000379:methods*; D006410:Hematopoiesis / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases