GATA3-controlled nucleosome eviction drives MYC enhancer activity in T-cell development and leukemia

Laura Belver, Alexander Y. Yang, Robert Albero, Daniel Herranz, Francesco G. Brundu, S. Aidan Quinn, Pablo Pérez-Durán, Silvia Álvarez, Francesca Gianni, Marissa Rashkovan, Devya Gurung, Pedro P. Rocha, Ramya Raviram, Clara Reglero, Jose R. Cortés, Anisha J. Cooke, Agnieszka A. Wendorff, Valentina Cordó, Jules P. Meijerink, Raúl RabadanAdolfo A. Ferrando

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

26 Citaten (Scopus)

Samenvatting

Long-range enhancers govern the temporal and spatial control of gene expression; however, the mechanisms that regulate enhancer activity during normal and malignant development remain poorly understood. Here, we demonstrate a role for aberrant chromatin accessibility in the regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, the NOTCH1-MYC enhancer (N-Me), a long-range T cell–specific MYC enhancer, shows dynamic changes in chromatin accessibility during T-cell specification and maturation and an aberrant high degree of chromatin accessibility in mouse and human T-ALL cells. Mechanistically, we demonstrate that GATA3-driven nucleosome eviction dynamically modulates N-Me enhancer activity and is strictly required for NOTCH1-induced T-ALL initiation and maintenance. These results directly implicate aberrant regulation of chromatin accessibility at oncogenic enhancers as a mechanism of leukemic transformation. SIGNIFICANCE: MYC is a major effector of NOTCH1 oncogenic programs in T-ALL. Here, we show a major role for GATA3-mediated enhancer nucleosome eviction as a driver of MYC expression and leukemic transformation. These results support the role of aberrant chromatin accessibility and consequent oncogenic MYC enhancer activation in NOTCH1-induced T-ALL.

Originele taal-2Engels
Pagina's (van-tot)1774-1791
Aantal pagina's18
TijdschriftCancer Discovery
Volume9
Nummer van het tijdschrift12
DOI's
StatusGepubliceerd - dec. 2019

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