急性髓系白血病 (AML) 通常与遗传异常有关，t (8;21) 易位导致融合癌蛋白 AML1-ETO (AE) 的产生，这种情况很常见。该蛋白在 t (8;21) AML 的发病、进展和复发中发挥着关键作用，使其成为治疗靶点。然而，针对AML1-ETO的药物分子的开发还明显不足，尤其是用于临床治疗的药物分子。在这项研究中，发现Neratinib可以显着下调AML1-ETO蛋白水平，从而促进t(8;21) AML细胞的分化。基于“差异化活性”探针，Neratinib 通过共价结合被鉴定为 HNRNPA3 的功能性抑制剂。进一步的研究表明，HNRNPA3 作为假定的 m6A 阅读器，负责识别和调节 AML-ETO 前 mRNA 的选择性剪接。这些发现不仅有助于对 AML1-ETO 转录物转录后修饰的调控机制产生新的见解，而且表明 Neratinib 在 t (8;21) AML 治疗中具有广阔的治疗潜力。版权所有 © 2024。由 Elsevier 出版B.V.

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.Copyright © 2024. Published by Elsevier B.V.