title: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.
abstract: 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 redistribution 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.
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: A
authors.initials: A
authors.lastname: Ptasinska
authors.forename: S A
authors.initials: SA
authors.lastname: Assi
authors.forename: D
authors.initials: D
authors.lastname: Mannari
authors.forename: S R
authors.initials: SR
authors.lastname: James
authors.forename: D
authors.initials: D
authors.lastname: Williamson
authors.forename: J
authors.initials: J
authors.lastname: Dunne
authors.forename: M
authors.initials: M
authors.lastname: Hoogenkamp
authors.forename: M
authors.initials: M
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Care
authors.forename: H
authors.initials: H
authors.lastname: McNeill
authors.forename: P
authors.initials: P
authors.lastname: Cauchy
authors.forename: M
authors.initials: M
authors.lastname: Cullen
authors.forename: R M
authors.initials: RM
authors.lastname: Tooze
authors.forename: D G
authors.initials: DG
authors.lastname: Tenen
authors.forename: B D
authors.initials: BD
authors.lastname: Young
authors.forename: P N
authors.initials: PN
authors.lastname: Cockerill
authors.forename: D R
authors.initials: DR
authors.lastname: Westhead
authors.forename: O
authors.initials: O
authors.lastname: Heidenreich
authors.forename: C
authors.initials: C
authors.lastname: Bonifer
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D016000:Cluster Analysis; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014178:Translocation, Genetic
chemical_list: D023081:CCAAT-Binding Factor; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D012319:RNA Polymerase II