Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells
Summary: Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723008057 |
| _version_ | 1797777993496526848 |
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| author | Fenghua Qian Shaneice K. Nettleford Jiayan Zhou Brooke E. Arner Molly A. Hall Arati Sharma Charyguly Annageldiyev Randy M. Rossi Diwakar B. Tukaramrao Deborpita Sarkar Shailaja Hegde Ujjawal H. Gandhi Emily R. Finch Laura Goodfield Michael D. Quickel David F. Claxton Robert F. Paulson K. Sandeep Prabhu |
| author_facet | Fenghua Qian Shaneice K. Nettleford Jiayan Zhou Brooke E. Arner Molly A. Hall Arati Sharma Charyguly Annageldiyev Randy M. Rossi Diwakar B. Tukaramrao Deborpita Sarkar Shailaja Hegde Ujjawal H. Gandhi Emily R. Finch Laura Goodfield Michael D. Quickel David F. Claxton Robert F. Paulson K. Sandeep Prabhu |
| author_sort | Fenghua Qian |
| collection | DOAJ |
| description | Summary: Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44−/− LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML. |
| first_indexed | 2024-03-12T23:11:55Z |
| format | Article |
| id | doaj.art-ce35a814bf814b97aa20a01a202f9e01 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T23:11:55Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ce35a814bf814b97aa20a01a202f9e012023-07-18T04:07:16ZengElsevierCell Reports2211-12472023-07-01427112794Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cellsFenghua Qian0Shaneice K. Nettleford1Jiayan Zhou2Brooke E. Arner3Molly A. Hall4Arati Sharma5Charyguly Annageldiyev6Randy M. Rossi7Diwakar B. Tukaramrao8Deborpita Sarkar9Shailaja Hegde10Ujjawal H. Gandhi11Emily R. Finch12Laura Goodfield13Michael D. Quickel14David F. Claxton15Robert F. Paulson16K. Sandeep Prabhu17Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USATransgenic Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USAHoxworth Blood Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USADepartment of Hematology and Oncology, University of North Carolina Health, Cary, NC 27518, USADepartment of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAImmunooncology Division, Bicycle Therapeutics, Boston, MA 02140, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USADepartment of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Corresponding authorDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Corresponding authorSummary: Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44−/− LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.http://www.sciencedirect.com/science/article/pii/S2211124723008057CP: Cancer |
| spellingShingle | Fenghua Qian Shaneice K. Nettleford Jiayan Zhou Brooke E. Arner Molly A. Hall Arati Sharma Charyguly Annageldiyev Randy M. Rossi Diwakar B. Tukaramrao Deborpita Sarkar Shailaja Hegde Ujjawal H. Gandhi Emily R. Finch Laura Goodfield Michael D. Quickel David F. Claxton Robert F. Paulson K. Sandeep Prabhu Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells Cell Reports CP: Cancer |
| title | Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells |
| title_full | Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells |
| title_fullStr | Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells |
| title_full_unstemmed | Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells |
| title_short | Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells |
| title_sort | activation of gpr44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723008057 |
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