C/EBPα and DEK coordinately regulate myeloid differentiation

Blood. 2012 May 24;119(21):4878-88. doi: 10.1182/blood-2011-10-383083. Epub 2012 Apr 3.


The transcription factor C/EBPα is a critical mediator of myeloid differentiation and is often functionally impaired in acute myeloid leukemia. Recent studies have suggested that oncogenic FLT3 activity disrupts wild-type C/EBPα function via phosphorylation on serine 21 (S21). Despite the apparent role of pS21 as a negative regulator of C/EBPα transcription activity, the mechanism by which phosphorylation tips the balance between transcriptionally competent and inhibited forms remains unresolved. In the present study, we used immuno-affinity purification combined with quantitative mass spectrometry to delineate the proteins associated with C/EBPα on chromatin. We identified DEK, a protein with genetic links to leukemia, as a member of the C/EBPα complexes, and demonstrate that this association is disrupted by S21 phosphorylation. We confirmed that DEK is recruited specifically to chromatin with C/EBPα to enhance GCSFR3 promoter activation. In addition, we demonstrated that genetic depletion of DEK reduces the ability of C/EBPα to drive the expression of granulocytic target genes in vitro and disrupts G-CSF-mediated granulocytic differentiation of fresh human BM-derived CD34(+) cells. Our data suggest that C/EBPα and DEK coordinately activate myeloid gene expression and that S21 phosphorylation on wild-type C/EBPα mediates protein interactions that regulate the differentiation capacity of hematopoietic progenitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • CCAAT-Enhancer-Binding Proteins / antagonists & inhibitors
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • CCAAT-Enhancer-Binding Proteins / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosomal Proteins, Non-Histone / physiology*
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Hematopoiesis / drug effects
  • Hematopoiesis / genetics
  • Humans
  • K562 Cells
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Myeloid Cells / physiology*
  • Oncogene Proteins / antagonists & inhibitors
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Oncogene Proteins / physiology*
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Poly-ADP-Ribose Binding Proteins
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / pharmacology


  • Antibodies
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Chromosomal Proteins, Non-Histone
  • Dek protein, human
  • Oncogene Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase Kinases