title: Screening of drugs to treat 8p11 myeloproliferative syndrome using patient-derived induced pluripotent stem cells with fusion gene CEP110-FGFR1.
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.
authors: Department of Pediatric Hematology/Oncology, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Shohei
authors: S
authors: Yamamoto
authors: Department of Pediatric Hematology/Oncology, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Makoto
authors: M
authors: Otsu
authors: Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Emiko
authors: E
authors: Matsuzaka
authors: Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Chieko
authors: C
authors: Konishi
authors: Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Haruna
authors: H
authors: Takagi
authors: Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Sachiyo
authors: S
authors: Hanada
authors: Department of Pediatric Hematology/Oncology, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Shinji
authors: S
authors: Mochizuki
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Hiromitsu
authors: H
authors: Nakauchi
authors: Center for Antibody and Vaccine, IMSUT Hospital, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Kohzoh
authors: K
authors: Imai
authors: Department of Pediatric Hematology/Oncology, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; National Hospital Organization Shinshu Ueda Medical Center, Ueda, Japan.
authors: Kohichiro
authors: K
authors: Tsuji
authors: Department of Pediatric Hematology/Oncology, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Advanced Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Yasuhiro
authors: Y
authors: Ebihara
mesh_terms: D000293:Adolescent; D001562:Benzimidazoles / Q000627:therapeutic use; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006410:Hematopoiesis; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011724:Pyridazines / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014178:Translocation, Genetic
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D007093:Imidazoles; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D015363:Quinolones; C545373:ponatinib; D000068877:Imatinib Mesylate; D051496:Receptor, Fibroblast Growth Factor, Type 1; C405614:CEP110-FGFR1 fusion protein, human; D019311:Staurosporine; C059539:midostaurin