Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [RNA-Seq]

ABSTRACT: The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing, DNAse1-sequencing and RNA-sequncing was used for the identification of a dynamic core transcriptional network in t(8;21) AML This submission represents the RNA-Seq component of the study

ORGANISM(S): Homo sapiens

SUBMITTER: Salam Assi

PROVIDER: E-GEOD-54478 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Ptasinska Anetta A Assi Salam A SA Martinez-Soria Natalia N Imperato Maria Rosaria MR Piper Jason J Cauchy Pierre P Pickin Anna A James Sally R SR Hoogenkamp Maarten M Williamson Dan D Wu Mengchu M Tenen Daniel G DG Ott Sascha S Westhead David R DR Cockerill Peter N PN Heidenreich Olaf O Bonifer Constanze C

Cell reports 20140918 6

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 ...[more]

PMID: 25242324

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Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the following subset Series: GSE29222: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [ChIP-Seq and DNAse-Hypersensitivity data] GSE29223: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [expression array data] GSE34540: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (ChIP-seq) GSE34594: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (Illumina expression) Refer to individual Series

Dataset Information

Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [RNA-Seq]

Publications

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

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