title: Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition.
abstract: Abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway has been observed in a variety of human cancers. Therefore, targeting of the mTOR pathway is an attractive strategy for cancer treatment and several mTOR inhibitors, including AZD8055 (AZD), a novel dual mTORC1/2 inhibitor, are currently in clinical trials. Although bone marrow (BM) suppression is one of the primary side effects of anticancer drugs, it is not known if pharmacological inhibition of dual mTORC1/2 affects BM hematopoietic stem and progenitor cells (HSPCs) function and plasticity. Here we report that dual inhibition of mTORC1/2 by AZD or its analogue (KU-63794) depletes mouse BM Lin(-)Sca-1(+)c-Kit(+) cells in cultures via the induction of apoptotic cell death. Subsequent colony-forming unit (CFU) assays revealed that inhibition of mTORC1/2 suppresses the clonogenic function of hematopoietic progenitor cells (HPCs) in a dose-dependent manner. Surprisingly, we found that dual inhibition of mTORC1/2 markedly inhibits the growth of day-14 cobblestone area-forming cells (CAFCs) but enhances the generation of day-35 CAFCs. Given the fact that day-14 and day-35 CAFCs are functional surrogates of HPCs and hematopoietic stem cells (HSCs), respectively, these results suggest that dual inhibition of mTORC1/2 may have distinct effects on HPCs versus HSCs.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Aimin
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA ; Department of Hematology, Tianjin First Center Hospital, Tianjin 300192, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Hematology, Tianjin First Center Hospital, Tianjin 300192, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA ; Research Services, Ralph H. Johnson VAMC, Charleston, SC, USA ; Cancer Genes and Molecular Regulation Program, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: LaRue
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Schulte
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA ; Cancer Genes and Molecular Regulation Program, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Wang