Hes1 suppresses acute myeloid leukemia development through FLT3 repression

• Published in: Leukemia 2015-03, Vol.29 (3), p.576-585
• Main Authors: Kato, T, Sakata-Yanagimoto, M, Nishikii, H, Ueno, M, Miyake, Y, Yokoyama, Y, Asabe, Y, Kamada, Y, Muto, H, Obara, N, Suzukawa, K, Hasegawa, Y, Kitabayashi, I, Uchida, K, Hirao, A, Yagita, H, Kageyama, R, Chiba, S
• Format: Article
• Language: English
• Subjects: 631/67/1990/283/1897; 631/80/86; Acute myeloid leukemia; Animals; Antibodies; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - deficiency; Basic Helix-Loop-Helix Transcription Factors - genetics; Cancer; Cancer Research; Cell Proliferation; Cells; Cellular signal transduction; Clonal deletion; Critical Care Medicine; Disease Models, Animal; Enhancer-of-split protein; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Flt3 protein; FLT3L protein; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Fusion protein; Gene deletion; Gene expression; Gene Expression Regulation, Leukemic; Genetic aspects; Health aspects; Hematology; HES1 gene; Homeodomain Proteins - genetics; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - deficiency; Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Leukemogenesis; Ligands; Lymphoma; Medical research; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Mutation; Myeloid leukemia; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; original-article; Phosphorylation; Phosphotransferases; Promoter Regions, Genetic; Protein Binding; Protein-tyrosine kinase; Proteins; Receptors, Notch - genetics; Receptors, Notch - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Signaling; Survival Analysis; Transcription Factor HES-1; Transcription factors; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.281

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.