Tumor-suppressive role for Notch signaling in acute myeloid leukemia

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860778
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: TAKAYASU Kato 筑波大学, 医学医療系, 助教 (20646591)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 急性骨髄性白血病 / Notchシグナル / FLT3

Outline of Final Research Achievements

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, and represses target gene expression. We report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development. 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. 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 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.

Free Research Field

造血器腫瘍