title: AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis.
abstract: Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Abhishek A
authors.initials: AA
authors.lastname: Singh
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Amit
authors.initials: A
authors.lastname: Mandoli
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Koen H M
authors.initials: KH
authors.lastname: Prange
authors.affiliation: Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
mesh_terms: D000107:Acetylation; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D059467:Transcriptome
chemical_list: C107844:AML1-ETO fusion protein, human; C095514:CBFbeta-MYH11 fusion protein; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D015514:Oncogene Proteins, Fusion; D050784:Proto-Oncogene Protein c-ets-1; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
keywords: AML; AML1-ETO; CBFB-MYH11; PML-RARA; RUNX1