Journal
CANCER DISCOVERY
Volume 9, Issue 12, Pages 1774-1791Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0471
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Funding
- NIH [R35 CA210065, U54 CA193313, R01 CA185486, U54 CA209997, P30 CA013696]
- Leukemia and Lymphoma Society postdoctoral fellowships
- U.S. NIH [K99/R00 CA197869]
- Alex's Lemonade Stand Foundation
- American-Italian Cancer Foundation
- Damon-Runyon Sohn Pediatric Cancer fellowship
- Lady Tata Memorial Trust fellowship
- Dutch Cancer League [KWF 2016-10355]
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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.
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