A Novel Aurora Kinase Inhibitor Attenuates Leukemic Cell Proliferation Induced by Mesenchymal Stem Cells

• Published in: Molecular therapy. Oncolytics 2020-09, Vol.18, p.491-503
• Main Authors: Wang, Jun-Dan, Zhang, Wei, Zhang, Jing-Wen, Zhang, Ling, Wang, Le-Xun, Zhou, Hong-Sheng, Long, Liang, Lu, Gui, Liu, Quentin, Long, Zi-Jie
• Format: Article
• Language: English
• Subjects: AML; Aurora kinase inhibitor; cell proliferation; leukemic microenvironment; Original
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2020.08.001

Acute myeloid leukemia (AML) mesenchymal stem cells (MSCs) play an essential role in protecting leukemic cells from chemotherapeutic agents through activating a wide range of adhesion molecules and cytokines. Thus, more attention should be paid to attenuate the protection of leukemic cells by MSCs. By examining the gene expression files of MSCs from healthy donors and AML patients through high-throughput microarrays, we found that interleukin (IL)-6 was an important cytokine secreted by AML MSCs to protect leukemic cells, contributing to disease progression. Strikingly, Aurora A (AURKA) was activated by IL-6, offering a new target to interfere with leukemia. Importantly, a novel AURKA inhibitor, PW21, showed excellent AURKA kinase inhibitory activities and attenuated the interaction of leukemic cells and the microenvironment. PW21 inhibited MSC-induced cell proliferation, colony formation, and migration, and it induced cell apoptosis. Mechanically, PW21 could inhibit IL-6 secreted by MSCs. Moreover, we found that PW21 displayed a strong anti-leukemia effect on non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) and murine MLL-AF9 leukemic models. PW21 significantly prolonged the survival of leukemic mice and eliminated the leukemic progenitor cells. AURKA inhibitor PW21 could provide a new approach for treatment of leukemia through blocking the protection by the leukemic microenvironment in clinical application. [Display omitted] Mesenchymal stem cells (MSCs) in the leukemic microenvironment play an essential role to promote leukemic cell survival, leading to chemotherapeutic resistance; therefore, how to attenuate the protection by MSCs in leukemic cells needs to be urgently investigated. In this study, the authors designed a novel AURKA inhibitor, PW21, which inhibited MSC-induced cell proliferation and colony formation. PW21 could be a new approach for leukemia treatment through blocking the protection stemming from MSCs.