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

Cancer Discov. 2019 Dec;9(12):1774-1791. doi: 10.1158/2159-8290.CD-19-0471. Epub 2019 Sep 13.


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.

MeSH terms

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


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