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

  • Cell Rep. 2023 Jul 16;42(7):112794. doi: 10.1016/j.celrep.2023.112794.
Fenghua Qian  1 ,  Shaneice K Nettleford  1 ,  Jiayan Zhou  1 ,  Brooke E Arner  1 ,  Molly A Hall  1 ,  Arati Sharma  2 ,  Charyguly Annageldiyev  2 ,  Randy M Rossi  3 ,  Diwakar B Tukaramrao  2 ,  Deborpita Sarkar  1 ,  Shailaja Hegde  4 ,  Ujjawal H Gandhi  5 ,  Emily R Finch  6 ,  Laura Goodfield  7 ,  Michael D Quickel  1 ,  David F Claxton  2 ,  Robert F Paulson  8 ,  K Sandeep Prabhu  9
Affiliations
  • 1. Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
  • 2. Department of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • 3. Transgenic Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
  • 4. 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.
  • 5. Department of Hematology and Oncology, University of North Carolina Health, Cary, NC 27518, USA.
  • 6. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 7. Immunooncology Division, Bicycle Therapeutics, Boston, MA 02140, USA.
  • 8. Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: [email protected].
  • 9. Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: [email protected].
PMID: 37459233 DOI: 10.1016/j.celrep.2023.112794
Abstract

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.

Keywords
CP: Cancer; CRTH2; KRAS; MAP kinase; PPAR; RTK; leukemia; p53; prostaglandins; selenium.
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