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
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.
