Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells

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

Cell Reports (Jul 2023)

Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells

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

Affiliations

Fenghua Qian: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Shaneice K. Nettleford: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Jiayan Zhou: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Brooke E. Arner: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Molly A. Hall: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Arati Sharma: Department of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Charyguly Annageldiyev: Department of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Randy M. Rossi: Transgenic Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Diwakar B. Tukaramrao: Department of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Deborpita Sarkar: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
Shailaja Hegde: Hoxworth Blood Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Ujjawal H. Gandhi: Department of Hematology and Oncology, University of North Carolina Health, Cary, NC 27518, USA
Emily R. Finch: Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Laura Goodfield: Immunooncology Division, Bicycle Therapeutics, Boston, MA 02140, USA
Michael D. Quickel: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
David F. Claxton: Department of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Robert F. Paulson: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Corresponding author
K. Sandeep Prabhu: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 7
p. 112794

Abstract

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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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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