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

Oncogene. 2016 Apr 14;35(15):1965-76. doi: 10.1038/onc.2015.261. Epub 2015 Jul 6.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 16 / genetics*
  • Chromosomes, Human, Pair 16 / ultrastructure
  • Chromosomes, Human, Pair 21 / genetics*
  • Chromosomes, Human, Pair 21 / ultrastructure
  • Dimerization
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic / genetics*
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Acute / physiopathology
  • Leukemia, Myelomonocytic, Acute / genetics*
  • Leukemia, Myelomonocytic, Acute / pathology
  • Leukemia, Myelomonocytic, Acute / physiopathology
  • Multiprotein Complexes
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Interaction Mapping
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA-Binding Protein FUS / antagonists & inhibitors
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / physiology*
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Translocation, Genetic*
  • Tretinoin / pharmacology
  • Tretinoin / physiology*
  • U937 Cells

Substances

  • Multiprotein Complexes
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • RARA protein, human
  • RNA, Small Interfering
  • RNA-Binding Protein FUS
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • TLS-ERG fusion protein, human
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1
  • Tretinoin