Histone deacetylase inhibition sensitizes p53-deficient B-cell precursor acute lymphoblastic leukemia to chemotherapy.
Haematologica
; 109(6): 1755-1765, 2024 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-38124624
ABSTRACT
In pediatric acute lymphoblastic leukemia (ALL), mutations/deletions affecting the TP53 gene are rare at diagnosis. However, at relapse about 12% of patients show TP53 aberrations, which are predictive of a very poor outcome. Since p53-mediated apoptosis is an endpoint for many cytotoxic drugs, loss of p53 function frequently leads to therapy failure. In this study we show that CRISPR/Cas9-induced loss of TP53 drives resistance to a large majority of drugs used to treat relapsed ALL, including novel agents such as inotuzumab ozogamicin. Using a high-throughput drug screen, we identified the histone deacetylase inhibitor romidepsin as a potent sensitizer of drug responsiveness, improving sensitivity to all chemotherapies tested. In addition, romidepsin improved the response to cytarabine in TP53-deleted ALL cells in vivo. Together, these results indicate that the histone deacetylase inhibitor romidepsin can improve the efficacy of salvage therapies for relapsed TP53-mutated leukemia. Since romidepsin has been approved for clinical use in some adult malignancies, these findings may be rapidly translated to clinical practice.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia-Linfoma Linfoblástico de Células Precursoras B
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Proteína Supressora de Tumor p53
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Depsipeptídeos
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Inibidores de Histona Desacetilases
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article