@article{35328829936f4c84b40d97c0a3d4da48,
title = "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.",
author = "Laura Belver and Yang, {Alexander Y.} and Robert Albero and Daniel Herranz and Brundu, {Francesco G.} and Quinn, {S. Aidan} and Pablo P{\'e}rez-Dur{\'a}n and Silvia {\'A}lvarez and Francesca Gianni and Marissa Rashkovan and Devya Gurung and Rocha, {Pedro P.} and Ramya Raviram and Clara Reglero and Cort{\'e}s, {Jose R.} and Cooke, {Anisha J.} and Wendorff, {Agnieszka A.} and Valentina Cord{\'o} and Meijerink, {Jules P.} and Ra{\'u}l Rabadan and Ferrando, {Adolfo A.}",
note = "Funding Information: R. Rabadan is a member of the scientific advisory board at Aimedbio. A.A. Ferrando is a consultant at Ayala Pharmaceuticals and Spring-Works Therapeutics, reports receiving commercial research grants from Pfizer, Bristol-Myers Squibb, Merck, and Eli Lilly, and reports receiving other commercial research support from Novartis, EMD Millipore, and Applied Biological Materials. No potential conflicts of interest were disclosed by the other authors. Funding Information: We are grateful to T. Ludwig (The Ohio State University Comprehensive Cancer Center) for the Rosa26+/Cre-ERT2 mouse. We thank Esperanza Agullo-Pascual, Sofie Demeyer, Victor Lin, and Beatrix Ueberheide for outstanding technical assistance. This work was supported by the NIH grants R35 CA210065 (to A.A. Fernando), U54 CA193313 (to R. Rabad{\'a}n), R01 CA185486 (to R. Rabad{\'a}n), U54 CA209997 (to R. Rabad{\'a}n), and P30 CA013696 (Confocal and Specialized Microscopy Shared Resource and Transgenic Animal Shared Resource, Molecular Pathology Shared Resource, Herbert Irving Comprehensive Cancer Center). R. Albero and S. Alvarez are supported by Leukemia and Lymphoma Society postdoctoral fellowships. D. Herranz is supported by the U.S. NIH grant K99/R00 CA197869 and an Alex{\textquoteright}s Lemonade Stand Foundation Young Investigator grant. F. Gianni is supported by the American-Italian Cancer Foundation postdoctoral fellowship. M. Rashkovan is supported by a Damon-Runyon Sohn Pediatric Cancer fellowship. J.R. Cortes is supported by a Lady Tata Memorial Trust fellowship. V. Cord{\'o} is supported by the Dutch Cancer League (KWF 2016-10355). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Funding Information: We are grateful to T. Ludwig (The Ohio State University Comprehensive Cancer Center) for the Rosa26+/Cre-ERT2 mouse. We thank Esperanza Agullo-Pascual, Sofie Demeyer, Victor Lin, and Beatrix Ueberheide for outstanding technical assistance. This work was supported by the NIH grants R35 CA210065 (to A.A. Fernando), U54 CA193313 (to R. Rabad{\'a}n), R01 CA185486 (to R. Rabad{\'a}n), U54 CA209997 (to R. Rabad{\'a}n), and P30 CA013696 (Confocal and Specialized Microscopy Shared Resource and Transgenic Animal Shared Resource, Molecular Pathology Shared Resource, Herbert Irving Comprehensive Cancer Center). R. Albero and S. Alvarez are supported by Leukemia and Lymphoma Society postdoctoral fellowships. D. Herranz is supported by the U.S. NIH grant K99/R00 CA197869 and an Alex{\textquoteright}s Lemonade Stand Foundation Young Investigator grant. F. Gianni is supported by the American-Italian Cancer Foundation postdoctoral fellowship. M. Rashkovan is supported by a Damon-Runyon Sohn Pediatric Cancer fellowship. J.R. Cortes is supported by a Lady Tata Memorial Trust fellowship. V. Cord{\'o} is supported by the Dutch Cancer League (KWF 2016-10355). Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
month = dec,
doi = "10.1158/2159-8290.CD-19-0471",
language = "English (US)",
volume = "9",
pages = "1774--1791",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "12",
}