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Chronic Myeloid Leukemia
Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):483-494
Takashi Yahata,1,2*Abd Aziz Ibrahim,1,3* Ken-ichi Hirano,1,4 Yukari Muguruma,5 Kazuhito Naka,6 Katsuto Hozumi,1,4 Douglas E. Vaughan,7 Toshio Miyata8 and Kiyoshi Ando1,3
1Research Center for Regenerative Medicine, Tokai University School of Medicine, Kanagawa; Japan; 2Department of Innovative Medical Science, Tokai University School of Medicine, Kanagawa; Japan; 3Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan; 4Department of Immunology, Tokai University School of Medicine, Kanagawa; Japan; 5National Cancer Center Research Institute, Tokyo, Japan; 6Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; 7Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA and 8United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
*TY and AAI contributed equally as co-first authors.
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 acti- vator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSC to tyro- sine 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-β−PAI-1 axis was selectively augmented in CML- LSC 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, indi- cating the elimination of CML-LSC. Interestingly, PAI-1 inhibitor treatment augmented membrane-type matrix metalloprotease-1 (MT1-MMP)-depen- dent 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.
Introduction
Chronic myeloid leukemia (CML) was the first luekemia to be identified with a specific tumorigenic chromosomal abnormality - the Philadelphia chromosome.1 Subsequent studies identified that the translocation event, occurred between t(9;22) (q34;q11), fused the breakpoint cluster region gene (BCR) with the Abelson kinase gene (ABL1) and produced the BCR/ABL oncogene.2,3 This BCR/ABL fusion protein possesses constitutive tyrosine kinase activity resulting in the development of myeloid leukemia through aberrant differentiation of hematopoietic stem/progeni- tor cells (HSPC) toward the myeloid lineage. Although development of tyrosine kinase inhibitors (TKI) that target the abnormal activation of tyrosine kinase, such as imatinib, has dramatically improved the prognosis of CML,4,5 the disease often relapses, even after complete remission achieved under TKI therapy, thus remaining a central problem in the treatment of CML. It has been hypothesized that leukemic stem cells (LSC), also identified as leukemic initiating cells, are the cells that possess the unique ability to resist the cytotoxic agents and are responsible for the relapse of leukemia,6–8 highlighting the need for therapeutic strategies that specifically tar- get this population of cells.
Correspondence:
TAKASHI YAHATA
yahata@tokai-u.jp
Received: June 23, 2019. Accepted: January 24, 2020. Pre-published: January 30, 2020.
https://doi.org/10.3324/haematol.2019.230227
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