Screening of drugs to treat 8p11 myeloproliferative syndrome using patient-derived induced pluripotent stem cells with fusion gene CEP110-FGFR1

PLoS One. 2015 Mar 24;10(3):e0120841. doi: 10.1371/journal.pone.0120841. eCollection 2015.

Abstract

Induced pluripotent stem (iPS) cells provide powerful tools for studying disease mechanisms and developing therapies for diseases. The 8p11 myeloproliferative syndrome (EMS) is an aggressive chronic myeloproliferative disorder (MPD) that is caused by constitutive activation of fibroblast growth factor receptor 1. EMS is rare and, consequently, effective treatment for this disease has not been established. Here, iPS cells were generated from an EMS patient (EMS-iPS cells) to assist the development of effective therapies for EMS. When iPS cells were co-cultured with murine embryonic stromal cells, EMS-iPS cells produced more hematopoietic progenitor and hematopoietic cells, and CD34+ cells derived from EMS-iPS cells exhibited 3.2-7.2-fold more macrophage and erythroid colony forming units (CFUs) than those derived from control iPS cells. These data indicate that EMS-iPS cells have an increased hematopoietic differentiation capacity, which is characteristic of MPDs. To determine whether a tyrosine kinase inhibitor (TKI) could suppress the increased number of CFUs formed by EMS-iPS-induced CD34+ cells, cells were treated with one of four TKIs (CHIR258, PKC 412, ponatinib, and imatinib). CHIR258, PKC 412, and ponatinib reduced the number of CFUs formed by EMS-iPS-induced CD34+ cells in a dose-dependent manner, whereas imatinib did not. Similar effects were observed on primary peripheral blood cells (more than 90% of which were blasts) isolated from the patient. This study provides evidence that the EMS-iPS cell line is a useful tool for the screening of drugs to treat EMS and to investigate the mechanism underlying this disease.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Benzimidazoles / therapeutic use
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Hematopoiesis
  • Humans
  • Imatinib Mesylate / therapeutic use
  • Imidazoles / therapeutic use
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / pathology
  • Oncogene Proteins, Fusion / genetics*
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridazines / therapeutic use
  • Quinolones / therapeutic use
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Staurosporine / analogs & derivatives
  • Staurosporine / therapeutic use
  • Translocation, Genetic*

Substances

  • 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
  • Benzimidazoles
  • Imidazoles
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Pyridazines
  • Quinolones
  • ponatinib
  • Imatinib Mesylate
  • Receptor, Fibroblast Growth Factor, Type 1
  • CEP110-FGFR1 fusion protein, human
  • Staurosporine
  • midostaurin

Grants and funding

This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Y.E.), and the project for realization of regenerative medicine (Y.E.) and Research on Applying Health Technology, Health and Labour Sciences Research Grant, Ministry of Health, Labor and Welfare, Japan (K.I.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.