201. Neratinib impairs function of m6A recognition on AML1-ETO pre-mRNA and induces differentiation of t (8;21) AML cells by targeting HNRNPA3.
- Author
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Liu, Yulin, Zheng, Liting, Li, Ying, Ma, Lan, Zheng, Nan, Liu, Xinhua, Zhao, Yanli, Yu, Li, Liu, Ning, Liu, Shuangwei, Zhang, Kun, Zhou, Jingfeng, Wei, Mingming, Yang, Cheng, and Yang, Guang
- Subjects
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ALTERNATIVE RNA splicing , *ACUTE myeloid leukemia , *DRUG development - Abstract
Acute myeloid leukemia (AML) is frequently linked to genetic abnormalities, with the t (8; 21) translocation, resulting in the production of a fusion oncoprotein AML1-ETO (AE), being a prevalent occurrence. This protein plays a pivotal role in t (8; 21) AML's onset, advancement, and recurrence, making it a therapeutic target. However, the development of drug molecules targeting AML1-ETO are markedly insufficient, especially used in clinical treatment. In this study, it was uncovered that Neratinib could significantly downregulate AML1-ETO protein level, subsequently promoting differentiation of t (8; 21) AML cells. Based on "differentiated active" probes, Neratinib was identified as a functional inhibitor against HNRNPA3 through covalent binding. The further studies demonstrated that HNRNPA3 function as a putative m6A reader responsible for recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. These findings not only contribute to a novel insight to the mechanism governing post-transcriptional modification of AML1-ETO transcript, but also suggest that Neratinib would be promising therapeutic potential for t (8; 21) AML treatment. [Display omitted] • Neratinib could down-regulate the expression of AML1-ETO and induce differentiation of t (8; 21) AML cells. • Neratinib was identified as inhibitor against HNRNPA3, which was identified as m6A reader. • Neratinib targeted HNRNPA3 to impair its recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. • Neratinib could significantly triggered the differentiation of patients' primary AML cells. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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