TM5614, an Inhibitor of Plasminogen Activator Inhibitor-1, Exerts an Antitumor Effect on Chronic Myeloid Leukemia

TM5614, an Inhibitor of Plasminogen Activator Inhibitor-1, Exerts an Antitumor Effect on Chronic Myeloid Leukemia

Katsuyuki Sasaki,^1,2 Tohru Fujiwara,^1,2 Tetsuro Ochi,¹ Koya Ono,¹ Hiroki Kato,¹ Koichi Onodera,¹ Satoshi Ichikawa,¹ Noriko Fukuhara,¹ Yasushi Onishi,¹ Hisayuki Yokoyama,¹ Toshio Miyata³ and Hideo Harigae^1,2

¹Department of Hematology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
²Laboratory Diagnostics, Tohoku University Hospital, Sendai, Miyagi, Japan
³Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Sendai, Miyagi, Japan

Chronic myeloid leukemia (CML) is triggered by t(9;22)(q34;q11.2) translocation, leading to the formation of the BCR-ABL1 fusion gene. Although the development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has dramatically improved the prognosis of CML, the disease could often relapse, presumably because leukemic stem cell fraction of CML (CML-LSC) may reside in specific niches, and also acquire an ability to resist the cytotoxic agents. Recently a study indicated that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1, also known as SERPINE1) would cause detachment of CML-LSCs from their niche by inducing maturation of membrane-type matrix metalloprotease-1 (MT1-MMP), leading to increased susceptibility of CML-LSCs against TKIs. However, the direct antitumor effect of PAI-1 inhibition in CML remains unclear. Because PAI-1 mRNA expression was lower in CML cell line (K562) than bone marrow mononuclear cells derived from CML patients, we established K562 cell clones stably expressing exogenous PAI-1 (K562/PAI-1). We found that TM5614 treatment significantly suppressed cell proliferation and induced apoptosis in K562/PAI-1 cells, accompanied by increased activity of Furin protease, which is a known target of PAI-1. Besides processing mature MT1-MMP, Furin is in charge of cleaving the NOTCH receptor to form a heterodimer before exporting it to the cell surface membrane. In K562/PAI-1 cells, TM5614 treatment increased NOTCH1 intracellular domain (NICD) protein expression as well as NOTCH1 target of HEY1 mRNA levels. Finally, forced expression of either Furin or NICD in K562/PAI-1 cells significantly inhibited cell proliferation and induced apoptosis. Collectively, PAI-1 inhibition may have an antitumor effect by modulating the Furin/NICD pathway.

Keywords —— chronic myeloid leukemia; FURIN; NOTCH1 signaling; plasminogen activator inhibitor-1; TM5614

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Tohoku J. Exp. Med 2022, 257, 211-224.

Correspondence: Tohru Fujiwara, M.D., Ph.D., Laboratory Diagnostics, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: fujiwara-to@med.tohoku.ac.jp