Cell Mol Life Sci. 2023 Dec 16;81(1):10. doi: 10.1007/s00018-023-05036-8.
题目：
miR-181a plays the tumor-suppressor role in chronic myeloid leukemia CD34+ cells partially via SERPINE1
作者：
Xiuyan Zhang1,2,†, Wenjuan Ma1, Wen Xue1,3, Yu Wang1,4, Pan Chen1, Quanxue Li5, Yuan-Yuan Li5, Xiaohui Hu2,6,†, Yun Zhao1,6,7,†, Haixia Zhou2,6,†
单位：
1 Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China
2 The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China
3 The Affiliated Nanhua Hospital, Department of Clinical Research Institute, Hengyang Medical School, University of South China, Hengyang 421002, China
4 Jianhu Country People’s Hospital, Yancheng 224700, China
5 Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China,
6 National Clinical Research Center for Hematologic Diseases, Suzhou 215006, China
7 MOE Engineering Center of Hematological Disease, Soochow University, Suzhou 215123, China
摘要：
The formation of the BCR-ABL fusion gene drives human chronic myeloid leukemia (CML). The last 2 decades have witnessed that specific tyrosine kinase inhibitors (TKIs, e.g., imatinib mesylate, IM) against ABL1 improve disease treatment, although some patients still suffer from relapse and TKI resistance. Therefore, a better understanding of the molecular pathology of CML is still urgently needed. miR-181a-5p (miR-181a) acts as a tumor suppressor in CML; however, the molecular mechanism of miR-181a in CML stem/progenitor cells remains elusive. Herein, we showed that miR-181a inhibited the growth of CML CD34+ cells, including the quiescent subset, and sensitized them to IM treatment, while miR-181a inhibition by a sponge sequence collaborated with BCR-ABL to enhance the growth of normal CD34+ cells. Transcriptome data and biochemical analysis revealed that SERPINE1 was a bona fide and critical target of miR-181a, which deepened the understanding of the regulatory mechanism of SERPINE1. Genetic and pharmacological inhibition of SERPINE1 led to apoptosis mainly mediated by caspase-9 activation. The dual inhibition of SERPINE1 and BCR-ABL exhibited a significantly stronger inhibitory effect than a single agent. Taken together, this study demonstrates that a novel miR-181a/SERPINE1 axis modulates CML stem/progenitor cells, which likely provides an important approach to override TKI resistance.
全文链接：https://link.springer.com/article/10.1007/s00018-023-05036-8