GATA3-Controlled Nucleosome Eviction Drives MYC Enhancer Activity in T-cell Development and Leukemia.

Abstract

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.This article is highlighted in the In This Issue feature, p. 1631.

• Authors: 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 Rabadan, Adolfo A Ferrando
• Journal: Cancer discovery (Cancer Discov) Vol. 9 Issue 12 Pg. 1774-1791 (12 2019) ISSN: 2159-8290 [Electronic] United States
• PMID: 31519704 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• GATA3 Transcription Factor
• GATA3 protein, human
• MYC protein, human
• NOTCH1 protein, human
• Nucleosomes
• Proto-Oncogene Proteins c-myc
• Receptor, Notch1

Topics

• Animals
• Cell Line, Tumor
• Enhancer Elements, Genetic
• GATA3 Transcription Factor (metabolism)
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Jurkat Cells
• Leukemia, T-Cell (genetics, metabolism, pathology)
• Mice
• Neoplasm Transplantation
• Nucleosomes (metabolism)
• Proto-Oncogene Proteins c-myc (genetics)
• Receptor, Notch1 (metabolism)