Ontology type: schema:ScholarlyArticle
2015-03
AUTHORST 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
ABSTRACTIn 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. More... »
PAGES576
http://scigraph.springernature.com/pub.10.1038/leu.2014.281
DOIhttp://dx.doi.org/10.1038/leu.2014.281
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PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/25234168
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