title: Hes1 suppresses acute myeloid leukemia development through FLT3 repression.
abstract: In leukemogenesis, Notch signaling can be up and downregulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well-characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here, we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. FLT3 was consequently upregulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing messenger RNA (mRNA) expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by downregulating FLT3 expression.
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan [2] Life Science center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan [3] Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan [2] Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nishikii
authors.affiliation: Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Asabe
authors.affiliation: Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan [2] Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Muto
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan [2] Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Obara
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Suzukawa
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan [2] Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Kitabayashi
authors.affiliation: Department of Molecular Biological Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Hirao
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.affiliation: 1] Institute of Virus Research, Kyoto University, Kyoto, Japan [2] World Premier International Research Initiative-Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kageyama
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan [2] Life Science center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan [3] Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Chiba
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D000072056:Transcription Factor HES-1; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D051941:fms-Like Tyrosine Kinase 3; C489734:Hes1 protein, mouse; C551356:MLL-AF9 fusion protein, mouse; C497571:Rbpj protein, mouse; C497971:Flt3 protein, mouse