Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal

• Published in: Cell reports (Cambridge) 2014-09, Vol.8 (6), p.1974-1988
• Main Authors: Ptasinska, Anetta, Assi, Salam A., Martinez-Soria, Natalia, Imperato, Maria Rosaria, Piper, Jason, Cauchy, Pierre, Pickin, Anna, James, Sally R., Hoogenkamp, Maarten, Williamson, Dan, Wu, Mengchu, Tenen, Daniel G., Ott, Sascha, Westhead, David R., Cockerill, Peter N., Heidenreich, Olaf, Bonifer, Constanze
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; CCAAT-Enhancer-Binding Protein-alpha - genetics; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cell Line, Tumor; Chromatin Immunoprecipitation; Chromosome Mapping; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit - metabolism; Gene Regulatory Networks; Humans; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; LIM Domain Proteins - metabolism; Protein Binding; Proto-Oncogene Proteins - metabolism; RNA Interference; RNA, Messenger - metabolism; RNA, Small Interfering; Sequence Analysis, RNA; Trans-Activators - metabolism; Translocation, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.08.024

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. [Display omitted] •RUNX1/ETO drives a t(8;21)-specific transcriptional network•RUNX1/ETO and RUNX1 dynamically compete for the same genomic sites•RUNX1/ETO targets transcription factor complexes that control differentiation•RUNX1/ETO depletion activates a transcriptional network dominated by C/EBPα Chromosomal rearrangements generate cancer-specific fusion genes that interfere with cell differentiation. Ptasinska et al. show that the most frequent fusion protein in acute myeloid leukemia (RUNX1/ETO) controls a cancer-propagating transcriptional network by binding to genomic sites in a dynamic equilibrium with wild-type RUNX1. Depletion of RUNX1/ETO installs a differentiation-promoting transcriptional network. Our findings demonstrate that the differentiation block in AML has a dynamic component as its core feature, which might provide a target for cancer-specific differentiation therapy.