Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells.

Abstract

Therapeutic strategies that target leukemic stem cells (LSC) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here we showed that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSC to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSC and leads to sustained remission of the disease. We demonstrated for the first time that the TGF-−PAI-1 axis was selectively augmented in CMLLSC in the bone marrow (BM), thereby protecting CML-LSC from TKI treatment. Furthermore, the combined administration of the TKI imatib plus a PAI-1 inhibitor, in a mouse model of CML, significantly enhanced the eradication of CML cells in the BM and prolonged the survival of CML mice. The combined therapy of imatinib and a PAI-1 inhibitor prevented the recurrence of CML-like disease in serially transplanted recipients, indicating the elimination of CML-LSC. Interestingly, PAI-1 inhibitor treatment augmented membrane-type matrix metalloprotease-1 (MT1-MMP)-dependent motility of CML-LSC, and the anti-CML effect of PAI-1 inhibitor was extinguished by the neutralizing antibody for MT1-MMP, underlining the mechanistic importance of MT1-MMP. Our findings provide evidence of, and a rationale for, a novel therapeutic tactic, based on the blockade of PAI- 1 activity, for CML patients.