Gata3-controlled nucleosome eviction drives Myc enhancer activity in T-cell development and leukemia.

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 Myc expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, N-Me, a long-range T-cell specific Myc enhancer shows dynamic changes in chromatin accessibility during T-cell specification and maturation and 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 mechanism of leukemia transformation.

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