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- Title
The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation.
- Authors
Domingo-Reinés, Joan; Montes, Rosa; Garcia-Moreno, Adrián; Gallardo, Amador; Sanchez-Manas, Jose Manuel; Ellson, Iván; Lamolda, Mar; Calabro, Chiara; López-Escamez, Jose Antonio; Catalina, Purificación; Carmona-Sáez, Pedro; Real, Pedro J.; Landeira, David; Ramos-Mejia, Verónica
- 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.
- Publication
Cell Death & Disease, 2023, Vol 14, Issue 6, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-023-05870-5