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

Rui Su; Chuting Li; Xiuyuan Wang; Zhendong Li; Ziqi Wen; Zhao Yin; Guiping Huang; Yanjun Liu; Juhua Yang; Haiyan Hu; Hong Nie; Keda Zhang; Jia Fei

doi:10.1016/j.omtn.2023.04.026

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

Mol Ther Nucleic Acids. 2023 May 4:32:729-742. doi: 10.1016/j.omtn.2023.04.026. eCollection 2023 Jun 13.

Authors

Rui Su^{1

2

3}, Chuting Li^{1

2

3}, Xiuyuan Wang^{1

2

3}, Zhendong Li⁴, Ziqi Wen^{1

2

3}, Zhao Yin^{1

2

3}, Guiping Huang^{1

2

3}, Yanjun Liu^{1

2

3}, Juhua Yang^{1

2

3}, Haiyan Hu^{5

6}, Hong Nie^{7

8}, Keda Zhang⁹, Jia Fei^{1

2

3}

Affiliations

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.

Abstract

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.

Keywords: BCR-ABL1-independent imatinib resistance; MT: Non-coding RNAs; PPFIA1; apoptosis; chronic myeloid leukemia; drug resistance; leukemia stem cells; mir-181a; small activating RNA (saRNA).