2. Academic Validation
  3. Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells

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

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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