Journal article
Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1
Cell stem cell, Vol.21(3), pp.359-373.e5
09/07/2017
DOI: 10.1016/j.stem.2017.08.001
PMCID: PMC5678929
PMID: 28844837
Abstract
Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34+ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a β-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML.
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•Signature-based query of connectivity maps identifies PGE1 as a CML LSC inhibitor•PGE1 targets AP-1 factors and impairs activity of CML LSCs in mice and humans•The synthetic EP4 receptor agonist misoprostol also impairs CML LSC activity•PGE1 enhances the efficacy of imatinib treatment in CML xenograft models
Xue and colleagues show that prostaglandin E1 (PGE1) inhibits the activity and self-renewal of human CML leukemic stem cells. Combination of PGE1 or an agonist for its receptor EP4 with conventional tyrosine kinase inhibitor treatment can effectively target CML leukemic stem cells and reduce leukemia growth.
Details
- Title: Subtitle
- Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1
- Creators
- Fengyin Li - University of IowaBing He - Children's Hospital of PhiladelphiaXiaoke Ma - Children's Hospital of PhiladelphiaShuyang Yu - China Agricultural UniversityRupali R. Bhave - Roy J. and Lucille A. Carver College of MedicineSteven R. Lentz - University of IowaKai Tan - Children's Hospital of PhiladelphiaMonica L. Guzman - Cornell UniversityChen Zhao - Roy J. and Lucille A. Carver College of MedicineHai-Hui Xue - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Cell stem cell, Vol.21(3), pp.359-373.e5
- DOI
- 10.1016/j.stem.2017.08.001
- PMID
- 28844837
- PMCID
- PMC5678929
- NLM abbreviation
- Cell Stem Cell
- ISSN
- 1934-5909
- eISSN
- 1875-9777
- Publisher
- Elsevier Inc
- Grant note
- name: Carver College of Medicine/Holden Comprehensive Cancer Center (the University of Iowa); name: Iowa City Veterans Administration Medical Center; DOI: 10.13039/100000097, name: National Center for Research Resources, award: 1S10 OD016199; DOI: 10.13039/100000002, name: NIH; name: NCI, award: P30CA086862; name: Carver College of Medicine (University of Iowa); DOI: 10.13039/100000002, name: NIH, award: AI112579, AI115149, AI119160, AI121080, HG006130, P50 CA097274; name: Veteran Affairs BLR&D Merit Review Program, award: BX002903A
- Language
- English
- Date published
- 09/07/2017
- Academic Unit
- Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Internal Medicine
- Record Identifier
- 9984359915302771
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