| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
|
|---|
| 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.
|
