Neratinib impairs function of m6A recognition on AML1-ETO pre-mRNA and induces differentiation of t (8;21) AML cells by targeting HNRNPA3.
Cancer Lett
; 594: 216980, 2024 Jul 10.
Article
em En
| MEDLINE
| ID: mdl-38797229
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Leucemia Mieloide Aguda
/
Proteínas de Fusão Oncogênica
/
Diferenciação Celular
/
Subunidade alfa 2 de Fator de Ligação ao Core
/
Proteína 1 Parceira de Translocação de RUNX1
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Lett
Ano de publicação:
2024
Tipo de documento:
Article