Elucidation of mechanism underlying cell cycle regulation and development of therapeutic strategy

2014 Fiscal Year Final Research Report

• Project Area: Development of Novel Treatment Strategies Targeting Cancer Stem Cells
• Project/Area Number: 22130003
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: NAKAYAMA Keiichi 九州大学, 生体防御医学研究所, 教授 (80291508)
• Co-Investigator(Kenkyū-buntansha): NISHIYAMA Masaaki 九州大学, 生体防御医学研究所, 助教 (50423562)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 癌幹細胞 / 細胞周期 / 静止期 / ユビキチンリガーゼ / CDKインヒビター

Outline of Final Research Achievements

Most cancer stem cells (CSCs) are quiescent, and this characteristic provides these cells with resistance to conventional anticancer therapies that preferentially target dividing cells. CSCs that persist in spite of therapies may result in relapses and metastases. Here we show that Fbxw7 and p57 play a pivotal role in maintenance of quiescence in leukemia-initiating cells (LICs) of chronic myeloid leukemia (CML). Our findings reveal that ablation of Fbxw7 or p57 in a mouse model of CML results in disruption of quiescence in LICs. Furthermore, we demonstrate that LICs lacking Fbxw7 or p57 are sensitive to currently available anticancer drugs and combination therapy with Fbxw7/p57 depletion and these drugs is able to eradicate LICs, leading to a decreased relapse rate and a significant survival advantage. Such combination therapy is also effective for human CML LICs, supporting our conclusion that Fbxw7 and p57 are promising targets for the treatment of human leukemia.

Free Research Field

分子生物学