title: Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML.
abstract: Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI1(36N)) instead of a serine at position 36 (GFI1(36S)), which is associated with de novo AML in humans. However, how GFI1(36N) predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1(36N) or GFI1(36S). Presence of GFI1(36N) shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1(36N) induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1(36N)-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1(36N)-induced AML can be targeted.
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Botezatu
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Michel
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Helness
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Vadnais
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Hönes
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada; Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Robert
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Vassen
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Aniththa
authors.initials: A
authors.lastname: Thivakaran
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Yahya
authors.initials: Y
authors.lastname: Al-Matary
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lams
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Schütte
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Görgens
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
authors.forename: Hind
authors.initials: H
authors.lastname: Medyouf
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciejewski
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada; Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada. Electronic address: Tarik.Moroy@ircm.qc.ca.
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address: cyrus.khandanpour@uk-essen.de.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khandanpour
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003062:Codon; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D056572:Histone Deacetylase Inhibitors; D014157:Transcription Factors; D006655:Histone Deacetylases