title: The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia.
abstract: The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Sotoca
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: K H M
authors.initials: KH
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: B
authors.initials: B
authors.lastname: Reijnders
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: L N
authors.initials: LN
authors.lastname: Nguyen
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: D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics* / Q000648:ultrastructure; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics* / Q000648:ultrastructure; D019281:Dimerization; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology*; D020298:U937 Cells; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D034702:RNA-Binding Protein FUS; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C000607071:RARA protein, human; C107302:TLS-ERG fusion protein, human