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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number112794
JournalCell Reports
Volume42
Issue number7
DOIs
StatePublished - Jul 25 2023

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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