Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition
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 inhib...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2015/561404 |
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| author | Aimin Yang Xia Xiao Mingfeng Zhao Amanda C. LaRue Bradley A. Schulte Gavin Y. Wang |
| author_facet | Aimin Yang Xia Xiao Mingfeng Zhao Amanda C. LaRue Bradley A. Schulte Gavin Y. Wang |
| author_sort | Aimin Yang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-073e9dca9d0b4219b7361eaf06a713e4 |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-073e9dca9d0b4219b7361eaf06a713e42025-02-03T06:13:06ZengWileyStem Cells International1687-966X1687-96782015-01-01201510.1155/2015/561404561404Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR InhibitionAimin Yang0Xia Xiao1Mingfeng Zhao2Amanda C. LaRue3Bradley A. Schulte4Gavin Y. Wang5Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Hematology, Tianjin First Center Hospital, Tianjin 300192, ChinaDepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USAAbnormal 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.http://dx.doi.org/10.1155/2015/561404 |
| spellingShingle | Aimin Yang Xia Xiao Mingfeng Zhao Amanda C. LaRue Bradley A. Schulte Gavin Y. Wang Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition Stem Cells International |
| title | Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition |
| title_full | Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition |
| title_fullStr | Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition |
| title_full_unstemmed | Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition |
| title_short | Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition |
| title_sort | differential reponses of hematopoietic stem and progenitor cells to mtor inhibition |
| url | http://dx.doi.org/10.1155/2015/561404 |
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