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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Cell Line, Tumor
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Chromosomes, Human, Pair 16 / genetics*
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Chromosomes, Human, Pair 16 / ultrastructure
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Chromosomes, Human, Pair 21 / genetics*
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Chromosomes, Human, Pair 21 / ultrastructure
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Dimerization
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Enhancer Elements, Genetic
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Gene Expression Regulation, Neoplastic / genetics*
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Hematopoiesis / physiology*
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Hematopoietic Stem Cells / pathology
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / pathology
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Leukemia, Myeloid, Acute / physiopathology
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Leukemia, Myelomonocytic, Acute / genetics*
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Leukemia, Myelomonocytic, Acute / pathology
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Leukemia, Myelomonocytic, Acute / physiopathology
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Multiprotein Complexes
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplastic Stem Cells / pathology
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Promoter Regions, Genetic
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Protein Binding
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Protein Interaction Mapping
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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RNA, Small Interfering / genetics
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RNA-Binding Protein FUS / antagonists & inhibitors
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RNA-Binding Protein FUS / genetics
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RNA-Binding Protein FUS / physiology*
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Receptors, Retinoic Acid / metabolism
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Retinoic Acid Receptor alpha
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Retinoid X Receptors / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Translocation, Genetic*
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Tretinoin / pharmacology
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Tretinoin / physiology*
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U937 Cells
Substances
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Multiprotein Complexes
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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RARA protein, human
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RNA, Small Interfering
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RNA-Binding Protein FUS
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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TLS-ERG fusion protein, human
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Trans-Activators
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Transcription Factors
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proto-oncogene protein Spi-1
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Tretinoin