Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML

Leukemia. 2010 May;24(5):914-23. doi: 10.1038/leu.2010.37. Epub 2010 Apr 8.


The transcription factor CCAAT enhancer-binding protein alpha (C/EBPalpha) has an important role in granulopoiesis. The tumor suppressor function of C/EBPalpha is shown by the findings that loss of expression or function of C/EBPalpha in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPalpha mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPalpha (C/EBPalpha-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPalpha-p30 in AML. In the present study, we show that C/EBPalpha-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPalpha-p30 results in recruitment of E2F1 in the PIN1 promoter. We show that the inhibition of PIN1 leads to myeloid differentiation in primary AML blasts with C/EBPalpha mutations. Overexpression of PIN1 in myeloid cells leads to block of granulocyte differentiation. We also show that PIN1 increases the stability of the c-Jun protein by inhibiting c-Jun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPalpha. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPalpha mutation.

Publication types

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

MeSH terms

  • Biomarkers, Tumor
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-alpha / physiology*
  • Cell Differentiation* / drug effects
  • Chromatin Immunoprecipitation
  • Flow Cytometry
  • Gene Expression Profiling
  • Granulocytes / cytology*
  • Granulocytes / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • K562 Cells
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mutation / genetics
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Oligonucleotide Array Sequence Analysis
  • Peptidylprolyl Isomerase / antagonists & inhibitors
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Promoter Regions, Genetic
  • Proteomics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin / metabolism


  • Biomarkers, Tumor
  • CCAAT-Enhancer-Binding Protein-alpha
  • NIMA-Interacting Peptidylprolyl Isomerase
  • RNA, Messenger
  • RNA, Small Interfering
  • Ubiquitin
  • JNK Mitogen-Activated Protein Kinases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase