| First Author | Qian F | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 7 | Pages | 112794 |
| PubMed ID | 37459233 | Mgi Jnum | J:338250 |
| Mgi Id | MGI:7510276 | Doi | 10.1016/j.celrep.2023.112794 |
| Citation | Qian F, et al. (2023) Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells. Cell Rep 42(7):112794 |
| abstractText | 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), Delta(12)-PGJ(2), and 15d-PGJ(2), 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. |
