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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alprostadil / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Cell Self Renewal / drug effects*
  • Drug Synergism
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Imatinib Mesylate / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Misoprostol / pharmacology*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism


  • Proto-Oncogene Proteins c-fos
  • Receptors, Prostaglandin E, EP4 Subtype
  • Transcription Factor AP-1
  • beta Catenin
  • Misoprostol
  • Imatinib Mesylate
  • Alprostadil