Enhancer engagement sustains oncogenic transformation and progression of B-cell precursor acute lymphoblastic leukemia.
J Exp Clin Cancer Res
; 43(1): 179, 2024 Jun 27.
Article
em En
| MEDLINE
| ID: mdl-38926853
ABSTRACT
BACKGROUND:
Enhancer reprogramming plays a significant role in the heterogeneity of cancer. However, we have limited knowledge about the impact of chromatin remodeling in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) patients, and how it affects tumorigenesis and drug response. Our research focuses on investigating the role of enhancers in sustaining oncogenic transformation in children with BCP-ALL.METHODS:
We used ATAC-seq to study the accessibility of chromatin in pediatric BCP-ALL at three different stages-onset, remission, and relapse. Using a combination of computational and experimental methods, we were able to analyze the accessibility landscape and focus on the most significant cis-regulatory sites. These sites were then functionally validated through the use of Promoter capture Hi-C in a primary cell line model called LAL-B, followed by RNA-seq and genomic deletion of target sites using CRISPR-Cas9 editing.RESULTS:
We found that enhancer activity changes during cancer progression and is mediated by the production of enhancer RNAs (eRNAs). CRISPR-Cas9-mediated validation of previously unknown eRNA productive enhancers demonstrated their capability to control the oncogenic activities of the MYB and DCTD genes.CONCLUSIONS:
Our findings directly support the notion that productive enhancer engagement is a crucial determinant of the BCP-ALL and highlight the potential of enhancers as therapeutic targets in pediatric BCP-ALL.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia-Linfoma Linfoblástico de Células Precursoras B
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Transformação Celular Neoplásica
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Elementos Facilitadores Genéticos
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Progressão da Doença
Limite:
Child
/
Humans
Idioma:
En
Revista:
J Exp Clin Cancer Res
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Itália