The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation.
Cell Death Dis
; 14(6): 357, 2023 06 10.
Article
em En
| MEDLINE
| ID: mdl-37301844
ABSTRACT
Pediatric Acute Myeloid Leukemia (AML) is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations. Despite the improvement of survival in the last years, about 50% of patients still experience a relapse. It is not possible to improve prognosis only with further intensification of chemotherapy, as come with a severe cost to the health of patients, often resulting in treatment-related death or long-term sequels. To design more effective and less toxic therapies we need a better understanding of pediatric AML biology. The NUP98-KDM5A chimeric protein is exclusively found in a particular subgroup of young pediatric AML patients with complex karyotypes and poor prognosis. In this study, we investigated the impact of NUP98-KDM5A expression on cellular processes in human Pluripotent Stem Cell models and a patient-derived cell line. We found that NUP98-KDM5A generates genomic instability through two complementary mechanisms that involve accumulation of DNA damage and direct interference of RAE1 activity during mitosis. Overall, our data support that NUP98-KDM5A promotes genomic instability and likely contributes to malignant transformation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Proteínas de Fusão Oncogênica
Tipo de estudo:
Risk_factors_studies
Limite:
Child
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article