GATA3-controlled nucleosome eviction drives MYC enhancer activity in T-cell development and leukemia
Belver, L. (Institute for Cancer Genetics. Columbia University)
Yang, A.Y. (Institute for Cancer Genetics. Columbia University)
Albero Gallego, Robert (Institute for Cancer Genetics. Columbia University)
Herranz, D. (Department of Pharmacology. Robert Wood Johnson Medical School. Rutgers University)
Brundu, F.G. (Department of Systems Biology. Columbia University)
Quinn, S.A. (Institute for Cancer Genetics. Columbia University)
Pérez-Durán, P. (Institute for Cancer Genetics. Columbia University)
Álvarez, S. (Institute for Cancer Genetics. Columbia University)
Gianni, F. (Institute for Cancer Genetics. Columbia University)
Rashkovan, M. (Institute for Cancer Genetics. Columbia University)
Gurung, D. (Institute for Cancer Genetics. Columbia University)
Rocha, P.P. (Division of Developmental Biology. Eunice Kennedy Shriver National Institute of Child Health and Human Development. NIH)
Raviram, R. (Department of Chemistry and Biochemistry. University of California. San Diego)
Reglero, C. (Institute for Cancer Genetics. Columbia University)
Cortés, J.R. (Institute for Cancer Genetics. Columbia University)
Cooke, A.J. (Institute for Cancer Genetics. Columbia University)
Wendorff, A.A. (Institute for Cancer Genetics. Columbia University)
Cordó, V. (Department of Pediatric Oncology. Hematology. Princess Maxima Center for Pediatric Oncology)
Meijerink, J.P. (Department of Pediatric Oncology. Hematology. Princess Maxima Center for Pediatric Oncology)
Rabadan, R. (Department of Biomedical Informatics. Columbia University)
Ferrando, A.A. (Department of Pathology. Columbia University Medical Center)

Fecha:	2019
Resumen:	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.
Derechos:	Aquest material està protegit per drets d'autor i/o drets afins. Podeu utilitzar aquest material en funció del que permet la legislació de drets d'autor i drets afins d'aplicació al vostre cas. Per a d'altres usos heu d'obtenir permís del(s) titular(s) de drets.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Animals ; Cell Line, Tumor ; Enhancer Elements, Genetic ; GATA3 Transcription Factor ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Jurkat Cells ; Leukemia, T-Cell ; Mice ; Neoplasm Transplantation ; Nucleosomes ; Proto-Oncogene Proteins c-myc ; Receptor, Notch1
Publicado en:	Cancer Discovery, Vol. 9 Núm. 12 (december 2019) , p. 1774-1791, ISSN 2159-8290

DOI: 10.1158/2159-8290.CD-19-0471
PMID: 31519704

Postprint 49 p, 9.1 MB

El registro aparece en las colecciones:
Artículos > Artículos de investigación
Artículos > Artículos publicados