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

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68 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1974-1988
Number of pages15
JournalCell Reports
Issue number6
Early online date18 Sept 2014
Publication statusPublished - 25 Sept 2014


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