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PAI-1 blockade eliminates leukemia stem cells
returning to the niche.17,20 Even in the presence of a PAI-1 inhibitor plus TKI, HSC should be able to return to the niche because they are refractory to TKI. On the contrary, TKI specifically targets CML cells once they are released from the niche. In fact, the PAI-1 inhibitor used in this study, has successfully completed a phase I trial without any noticeable adverse effects, including myelosupples- sion, and has advanced to the phase II trial. In summary, this study describes a novel role of iPAI-1 in drug-resis- tance in CML and suggests that the selective therapeutic targeting of this serpin may be of value in the treatment of patients with this malignant hematopoietic disorder.
Disclosures
The PAI-1 inhibitor used in this study is protected as intellec- tual property. TY, TM, and KA are listed as inventors in the patent application.
Contributions
TY and AAI designed research, performed experiments, ana- lyzed data, and co-wrote the paper; KH performed experiments;
KN provided study materials; MY and DEV wrote the paper; TM and KA conceived and designed the study.
Funding
TY, HK, and KA were supported by a grant-in-aid for Scientific Research and Strategic Research Foundation Grant- aided Project for private universities from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant number: 15H04301 and 17H03072); TY was also sup- ported by Project Research from the Tokai University School of Medicine, Takeda Science Foundation, and The Science Research Promotion Fund from The Promotion and Mutual Aid Corporation for private schools of Japan. AAI was supported by grant-in aid for young scientists from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant number: 18K14702). TY, TM, and KA were supported by the Project for Development of Innovative Research on Cancer Therapeutics (P- DIRECT) and the Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP), from the Japanese Agency for Medical Research and Development (grant number: 14533192, 12103262, and 14529205).
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