title: GFI1 as a novel prognostic and therapeutic factor for AML/MDS.
abstract: Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: J M
authors: JM
authors: Hönes
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: L
authors: L
authors: Botezatu
authors: Institut de recherches cliniques de Montréal (IRCM), Hematopoiesis and Cancer Research Unit, and Mc Gill University, Montréal, Canada.
authors: A
authors: A
authors: Helness
authors: Institut de recherches cliniques de Montréal (IRCM), Hematopoiesis and Cancer Research Unit, and Université de Montréal, Montréal, Canada.
authors: C
authors: C
authors: Vadnais
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: L
authors: L
authors: Vassen
authors: Institut de recherches cliniques de Montréal (IRCM), Chromatin and Genomic Expression Research Unit, and Université de Montréal, Montréal, Canada.
authors: F
authors: F
authors: Robert
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: S M
authors: SM
authors: Hergenhan
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: A
authors: A
authors: Thivakaran
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: J
authors: J
authors: Schütte
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Y S
authors: YS
authors: Al-Matary
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: R F
authors: RF
authors: Lams
authors: Institut de recherches cliniques de Montréal (IRCM), Hematopoiesis and Cancer Research Unit, and Université de Montréal, Montréal, Canada.
authors: J
authors: J
authors: Fraszscak
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, USA.
authors: H
authors: H
authors: Makishima
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, USA.
authors: T
authors: T
authors: Radivoyevitch
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, USA.
authors: B
authors: B
authors: Przychodzen
authors: Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
authors: S V
authors: SV
authors: da Conceição Castro
authors: Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: A
authors: A
authors: Görgens
authors: Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: B
authors: B
authors: Giebel
authors: Institute for Cell Biology (Tumor Research), University Hospital Essen, University Duisburg-Essen, Germany.
authors: L
authors: L
authors: Klein-Hitpass
authors: Institute for Cell Biology (Tumor Research), University Hospital Essen, University Duisburg-Essen, Germany.
authors: K
authors: K
authors: Lennartz
authors: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: M
authors: M
authors: Heuser
authors: Medical Clinic and Polyclinic, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors: C
authors: C
authors: Thiede
authors: Medical Clinic and Polyclinic, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors: G
authors: G
authors: Ehninger
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: U
authors: U
authors: Dührsen
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, USA.
authors: J P
authors: JP
authors: Maciejewski
authors: Institut de recherches cliniques de Montréal (IRCM), Hematopoiesis and Cancer Research Unit, and Université de Montréal, Montréal, Canada.|Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Canada.
authors: T
authors: T
authors: Möröy
authors: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: C
authors: C
authors: Khandanpour
mesh_terms: D000107:Acetylation; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000172:deficiency; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion; D011379:Prognosis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000172:deficiency
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C498275:GFI1 protein, human; D006657:Histones; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051548:Histone Acetyltransferases