2017 Fiscal Year Final Research Report
Blockade of PAI-1 eliminates leukemic stem cells
| Project/Area Number |
15H04301
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Tokai University |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
ANDO Kiyoshi 東海大学, 医学部, 教授 (70176014)
MIYATA Toshio 東北大学, 大学院・医学系研究科, 教授 (10222332)
IBRAHIM Abd Aziz 東海大学, 医学部, 特定研究員(PD) (50738789)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | 白血病 / 幹細胞 / ニッチ / 分子標的薬 / TGF-beta |
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| Outline of Final Research Achievements |
We found that the expression of TGF-b-iPAI-1 signaling was selectively augmented in CML stem cells. CML cells expressing higher levels of iPAI-1 were resistance to imatinib treatment, indicating the iPAI-1 protects CML cells from TKI treatment. Combined treatment of imatinib plus PAI-1 inhibitor significantly decreased the persistent CML cells in the BM, reduced spleen size, and prolonged survival of CML-bearing mice. Importantly, blockade of PAI-1 activity in combination with TKI effectively eliminated CML stem cells in the BM, which resulted in losing their ability to initiate CML disease in the serial transplanted recipients. The effect of PAI-1 inhibitor to enhance the therapeutic effect of TKI was completely canceled by the administration of neutralizing antibody specific for MT1-MMP. Our findings provide evidence that blockade of PAI-1 activity could be a novel therapeutic approach for CML patients.
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| Free Research Field |
幹細胞生物学
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