Role of Smad7 in myeloid leukemogenesis

2015 Fiscal Year Final Research Report

• Project/Area Number: 26830086
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Couzinet Arnaud 公益財団法人がん研究会, その他部局等, 研究員 (70725621)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: がん微小環境 / TGF-β / 白血病 / Meis 1 / Smad 7

Outline of Final Research Achievements

In acute myeloid leukemia, the transcription factor MEIS1 is critical for in vivo invasion and propagation of HOXA9-transformed leukemic cells. This project led to the discovery of Smad7 (a TGF-β signaling negative regulator) as a target gene of MEIS1. Inoculation into mice of bone marrow cells engineered to overexpress HOXA9 and Smad7 led to the onset of leukemia, demonstrating the ability for Smad7 to bypass MEIS1 absence and raising the possibility that TGF-β may be employed as a protective cytokine against acute myeloid leukemia. In vitro experiments confirmed the direct anti-proliferative impact of TGF-β treatment on leukemic cells. However, in vivo TGF-β inhibition gave discrepant results depending on the frequency of TGF-β inhibitor injection, demonstrating the high functional complexity for the activity of TGF-β. On the other hand, our Smad7 transgene did not inhibit TGF-β signaling in vitro, suggesting that Smad7 leukemogenecity could be due to another unknown function.

Free Research Field

Oncology