Hes1 suppresses acute myeloid leukemia development through FLT3 repression

T Kato; M Sakata-Yanagimoto; H Nishikii; M Ueno; Y Miyake; Y Yokoyama; Y Asabe; Y Kamada; H Muto; N Obara; K Suzukawa; Y Hasegawa; I Kitabayashi; K Uchida; A Hirao; H Yagita; R Kageyama; S Chiba

doi:10.1038/leu.2014.281

Hes1 suppresses acute myeloid leukemia development through FLT3 repression

Leukemia. 2015 Mar;29(3):576-85. doi: 10.1038/leu.2014.281. Epub 2014 Sep 19.

Authors

T Kato¹, M Sakata-Yanagimoto², H Nishikii³, M Ueno⁴, Y Miyake⁵, Y Yokoyama³, Y Asabe⁵, Y Kamada⁵, H Muto², N Obara², K Suzukawa³, Y Hasegawa², I Kitabayashi⁶, K Uchida⁷, A Hirao⁴, H Yagita⁸, R Kageyama⁹, S Chiba¹

Affiliations

¹ 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.
² 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.
³ Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁴ Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
⁵ Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
⁶ Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan.
⁷ Department of Molecular Biological Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁸ Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
⁹ 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.

PMID: 25234168
DOI: 10.1038/leu.2014.281

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / deficiency
Basic Helix-Loop-Helix Transcription Factors / genetics*
Cell Proliferation
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression Regulation, Leukemic*
Homeodomain Proteins / genetics*
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein / deficiency
Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / mortality
Leukemia, Myeloid, Acute / pathology
Mice
Mice, Transgenic
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism
Phosphorylation
Promoter Regions, Genetic
Protein Binding
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Notch / genetics
Receptors, Notch / metabolism
Signal Transduction
Survival Analysis
Transcription Factor HES-1
fms-Like Tyrosine Kinase 3 / genetics*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
Hes1 protein, mouse
Homeodomain Proteins
Immunoglobulin J Recombination Signal Sequence-Binding Protein
MLL-AF9 fusion protein, mouse
Oncogene Proteins, Fusion
RNA, Messenger
Rbpj protein, mouse
Receptors, Notch
Transcription Factor HES-1
Flt3 protein, mouse
fms-Like Tyrosine Kinase 3
Extracellular Signal-Regulated MAP Kinases