Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal

Anetta Ptasinska, Salam A. Assi, Natalia Martinez-Soria, Maria Rosaria Imperato, Jason Piper, Pierre Cauchy, Anna Pickin, Sally R. James, Maarten Hoogenkamp, Dan Williamson, Mengchu Wu, Daniel G. Tenen, Sascha Ott, David R. Westhead, Peter N. Cockerill, Olaf Heidenreich, Constanze Bonifer

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

81 Citaten (Scopus)

Samenvatting

Oncogenic transcription factors such as RUNX1/ETO, which is generated by the chromosomal translocation t(8;21), subvert normal blood cell development by impairing differentiation and driving malignant self-renewal. Here, we use digital footprinting and chromatin immunoprecipitation sequencing (ChIP-seq) to identify the core RUNX1/ETO-responsive transcriptional network of t(8;21) cells. We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion. Perturbation of this equilibrium in t(8;21) cells by RUNX1/ETO depletion leads to a global redistribution of transcription factor complexes within preexisting open chromatin, resulting in the formation of a transcriptional network that drives myeloid differentiation. Our work demonstrates on a genome-wide level that the extent of impaired myeloid differentiation in t(8;21) is controlled by the dynamic balance between RUNX1/ETO and RUNX1 activities through the repression of transcription factors that drive differentiation.

Originele taal-2Engels
Pagina's (van-tot)1974-1988
Aantal pagina's15
TijdschriftCell Reports
Volume8
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - 25 sep. 2014
Extern gepubliceerdJa

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