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Cell Stem Cell. 2017 Sep 7;21(3):359-373.e5. doi: 10.1016/j.stem.2017.08.001. Epub 2017 Aug 30.

Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1.

Author information

1
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
3
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, P.R. China.
4
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
5
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
6
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: chen-zhao@uiowa.edu.
7
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: hai-hui-xue@uiowa.edu.

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.

KEYWORDS:

AP-1 family transcription factors; Tcf1 and Lef1 transcription factors; chronic myeloid leukemia; connectivity map; leukemic stem cells; misoprostol; prostaglandin E1; self-renewal; tyrosine kinase inhibitors; xenograft

PMID:
28844837
PMCID:
PMC5678929
DOI:
10.1016/j.stem.2017.08.001
[Indexed for MEDLINE]
Free PMC Article

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