title: CBFB-MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia.
abstract: Different mechanisms for CBFβ-MYH11 function in acute myeloid leukemia with inv(16) have been proposed such as tethering of RUNX1 outside the nucleus, interference with transcription factor complex assembly and recruitment of histone deacetylases, all resulting in transcriptional repression of RUNX1 target genes. Here, through genome-wide CBFβ-MYH11-binding site analysis and quantitative interaction proteomics, we found that CBFβ-MYH11 localizes to RUNX1 occupied promoters, where it interacts with TAL1, FLI1 and TBP-associated factors (TAFs) in the context of the hematopoietic transcription factors ERG, GATA2 and PU.1/SPI1 and the coregulators EP300 and HDAC1. Transcriptional analysis revealed that upon fusion protein knockdown, a small subset of the CBFβ-MYH11 target genes show increased expression, confirming a role in transcriptional repression. However, the majority of CBFβ-MYH11 target genes, including genes implicated in hematopoietic stem cell self-renewal such as ID1, LMO1 and JAG1, are actively transcribed and repressed upon fusion protein knockdown. Together these results suggest an essential role for CBFβ-MYH11 in regulating the expression of genes involved in maintaining a stem cell phenotype.
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Mandoli
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Singh
authors.affiliation: Department of Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: P W T C
authors.initials: PW
authors.lastname: Jansen
authors.affiliation: 1] Department of Hematology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands [2] Department of Laboratory Medicine University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A T J
authors.initials: AT
authors.lastname: Wierenga
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Riahi
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Franci
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Prange
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Saeed
authors.affiliation: Department of Hematology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: Department of Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: H G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: J H A
authors.initials: JH
authors.lastname: Martens
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001665:Binding Sites; D007446:Chromosome Inversion; D002885:Chromosomes, Human, Pair 16; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D050658:Core Binding Factor beta Subunit / Q000502:physiology*; D050989:GATA2 Transcription Factor / Q000502:physiology; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D050989:GATA2 Transcription Factor; D006655:Histone Deacetylases; D018995:Myosin Heavy Chains; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C493692:CBFB protein, human; C078433:FLI1 protein, human; C494711:GATA2 protein, human; C509903:MYH11 protein, human; C493728:RUNX1 protein, human; C067143:TAL1 protein, human