title: The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs.
abstract: The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. Here, we have investigated its effects on the transcriptome and epigenome in t(8,21) patient cells. AML1-ETO binding was found at promoter regions of active genes with high levels of histone acetylation but also at distal elements characterized by low acetylation levels and binding of the hematopoietic transcription factors LYL1 and LMO2. In contrast, ERG, FLI1, TAL1, and RUNX1 bind at all AML1-ETO-occupied regulatory regions, including those of the AML1-ETO gene itself, suggesting their involvement in regulating AML1-ETO expression levels. While expression of AML1-ETO in myeloid differentiated induced pluripotent stem cells (iPSCs) induces leukemic characteristics, overexpression increases cell death. We find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together our results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells.
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: 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: Koen H M
authors.initials: KHM
authors.lastname: Prange
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Tijchon
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Oerlemans
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Dirks
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Ter Huurne
authors.affiliation: Department of Hematology, University of Groningen and University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen and University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, the Netherlands.
authors.forename: Albertus T J
authors.initials: ATJ
authors.lastname: Wierenga
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Janssen-Megens
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Berentsen
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Bowon
authors.initials: B
authors.lastname: Kim
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Luan N
authors.initials: LN
authors.lastname: Nguyen
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Nina C
authors.initials: NC
authors.lastname: Hubner
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Nagesha A
authors.initials: NA
authors.lastname: Rao
authors.affiliation: Sanquin Research Department of Hematopoiesis, P.O. Box 9190, 1006 AD Amsterdam, the Netherlands.
authors.forename: Emile
authors.initials: E
authors.lastname: van den Akker
authors.affiliation: Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico Luigi de Crecchio 7, 80138 Napoli, Italy; Istituto di Genetica e Biofisica "Adriano Buzzati Traverso," Via P. Castellino 131, 80131 Napoli, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Department of Hematology, University of Groningen and University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, the Netherlands.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands; Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico Luigi de Crecchio 7, 80138 Napoli, Italy. Electronic address: j.martens@ncmls.ru.nl.
authors.forename: Joost H A
authors.initials: JHA
authors.lastname: Martens
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006410:Hematopoiesis / Q000235:genetics*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D000071230:Transcriptional Regulator ERG; D006655:Histone Deacetylases
keywords: AML1-ETO; RUNX1; acute myeloid leukemia; apoptosis; epigenome; iPSC