title: Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal.
abstract: 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.
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Anetta
authors.initials: A
authors.lastname: Ptasinska
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Salam A
authors.initials: SA
authors.lastname: Assi
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Martinez-Soria
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Imperato
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Piper
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cauchy
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Pickin
authors.affiliation: Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Sally R
authors.initials: SR
authors.lastname: James
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hoogenkamp
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Williamson
authors.affiliation: Cancer Science Institute, National University of Singapore, Republic of Singapore, Singapore 117456, Singapore.
authors.forename: Mengchu
authors.initials: M
authors.lastname: Wu
authors.affiliation: Cancer Science Institute, National University of Singapore, Republic of Singapore, Singapore 117456, Singapore.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ott
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Westhead
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Cockerill
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK. Electronic address: olaf.heidenreich@ncl.ac.uk.
authors.forename: Olaf
authors.initials: O
authors.lastname: Heidenreich
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: c.bonifer@bham.ac.uk.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D053263:Gene Regulatory Networks; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D017423:Sequence Analysis, RNA; D015534:Trans-Activators / Q000378:metabolism; D014178:Translocation, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D022763:CCAAT-Enhancer-Binding Protein-alpha; D050676:Core Binding Factor Alpha 2 Subunit; D060588:LIM Domain Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C085117:LMO2 protein, human