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PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration

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资源类型：
Pubmed体系：
作者：
Su Rui[1,2,3] * ; Li Chuting[1,2,3] * ; Wang Xiuyuan[1,2,3] * ; Li Zhendong[4] * ; Wen Ziqi[1,2,3] ; Yin Zhao[1,2,3] ; Huang Guiping[1,2,3] ; Liu Yanjun[1,2,3] ; Yang Juhua[1,2,3] ; Hu Haiyan[5,6,*1] ; Nie Hong[7,8,*2] ; Zhang Keda[9,*3] ; Fei Jia[1,2,3,*4] ;
机构： [1]Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China. [2]Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China. [3]Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China. [4]Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong, China. [5]Clinical Trial Center of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. [6]Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. [7]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China. [8]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China. [9]College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
出处：
DOI： 10.1016/j.omtn.2023.04.026
ISSN：

摘要：
A large proportion of patients with chronic myeloid leukemia (CML; 20%-50%) develop resistance to imatinib in a BCR-ABL1-independent manner. Therefore, new therapeutic strategies for use in this subset of imatinib-resistant CML patients are urgently needed. In this study, we used a multi-omics approach to show that PPFIA1 was targeted by miR-181a. We demonstrate that both miR-181a and PPFIA1-siRNA reduced the cell viability and proliferative capacity of CML cells in vitro, as well as prolonged the survival of B-NDG mice harboring human BCR-ABL1-independent imatinib-resistant CML cells. Furthermore, treatment with miR-181a mimic and PPFIA1-siRNA inhibited the self-renewal of c-kit+ and CD34+ leukemic stem cells and promoted their apoptosis. Small activating (sa)RNAs targeting the promoter of miR-181a increased the expression of endogenous primitive miR-181a (pri-miR-181a). Transfection with saRNA 1-3 inhibited the proliferation of imatinib-sensitive and -resistant CML cells. However, only saRNA-3 showed a stronger and more sustained inhibitory effect than the miR-181a mimic. Collectively, these results show that miR-181a and PPFIA1-siRNA may overcome the imatinib resistance of BCR-ABL1-independent CML, partially by inhibiting the self-renewal of leukemia stem cells and promoting their apoptosis. Moreover, exogenous saRNAs represent promising therapeutic agents in the treatment of imatinib-resistant BCR-ABL1-independent CML.© 2023 The Author(s).

基金：
This work was supported by grants from The State Key Laboratory of Natural and Biomimetic Drugs (grant number K202113), Science and Technology Program of Guangdong Province (grant number 2017B 030303001), and Science and Technology Program of Guangzhou City (grant number 202206010063).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类 | 1 区 医学
小类 | 1 区 医学：研究与实验
最新[2025]版：
大类 | 2 区 医学
小类 | 2 区 医学：研究与实验
第一作者：
第一作者机构： [1]Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China. [2]Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China. [3]Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China.
共同第一作者：
通讯作者：
通讯机构： [1]Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China. [2]Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China. [3]Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China. [5]Clinical Trial Center of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. [6]Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. [7]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China. [8]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China. [9]College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China. [*1]Clinical trial center of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China. [*2]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China [*3]College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China. [*4]Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
推荐引用方式(GB/T 7714)：
Su Rui,Li Chuting,Wang Xiuyuan,et al.PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration[J].Molecular therapy. Nucleic acids.2023,32:729-742.doi:10.1016/j.omtn.2023.04.026.
APA：
Su Rui,Li Chuting,Wang Xiuyuan,Li Zhendong,Wen Ziqi...&Fei Jia.(2023).PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration.Molecular therapy. Nucleic acids,32,
MLA：
Su Rui,et al."PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration".Molecular therapy. Nucleic acids 32.(2023):729-742

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