<br>靶向 PPFIA1 的 miR-181a 模拟物和 saRNA 通过抑制白血病干细胞再生来克服 BCR-ABL1 非依赖性慢性粒细胞白血病中的伊马替尼耐药性,Molecular Therapy - Nucleic Acids

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靶向 PPFIA1 的 miR-181a 模拟物和 saRNA 通过抑制白血病干细胞再生来克服 BCR-ABL1 非依赖性慢性粒细胞白血病中的伊马替尼耐药性
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2023-05-04 , DOI: 10.1016/j.omtn.2023.04.026
Rui Su _{1,

2,

3} , Chuting Li _{1,

2,

3} , Xiuyuan Wang _{1,

2,

3} , Zhendong Li ₄ , 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 Zhang ₉ , Jia Fei _{1,

2,

3}

Affiliation

Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.
Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China.
Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China.
Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong, China.
Clinical Trial Center of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
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.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.

很大一部分慢性粒细胞白血病（CML;20%-50%）患者以 BCR-ABL1 非依赖性方式对伊马替尼产生耐药性。因此，迫切需要用于伊马替尼耐药 CML 患者亚群的新治疗策略。在这项研究中，我们使用多组学方法表明 PPFIA1 是 miR-181a 的靶点。我们证明 miR-181a 和 PPFIA1-siRNA 在体外降低了 CML 细胞的细胞活力和增殖能力，并延长了携带人 BCR-ABL1 非依赖性伊马替尼耐药 CML 细胞的 B-NDG 小鼠的存活。此外，miR-181a 模拟物和 PPFIA1-siRNA 处理抑制 c-kit+ 和 CD34+ 白血病干细胞的自我更新并促进其细胞凋亡。靶向 miR-181a 启动子的小激活（sa） RNA 增加了内源性原始 miR-181a （pri-miR-181a）的表达。转染 saRNA 1-3 可抑制伊马替尼敏感和耐药的 CML 细胞的增殖。然而，只有 saRNA-3 显示出比 miR-181a 模拟物更强、更持久的抑制作用。总的来说，这些结果表明，miR-181a 和 PPFIA1-siRNA 可能通过抑制白血病干细胞的自我更新和促进其凋亡来克服 BCR-ABL1 非依赖性 CML 的伊马替尼耐药性。此外，外源性 saRNAs 是治疗伊马替尼耐药 BCR-ABL1 非依赖性 CML 的有前途的治疗药物。

"点击查看英文标题和摘要"

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

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.

更新日期：2023-05-04

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