The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner

Oncogene. 2003 Aug 28;22(36):5646-57. doi: 10.1038/sj.onc.1206673.

Abstract

Overexpression of proto-oncogene c-jun and constitutive activation of the Jun N-terminal kinase (JNK) signaling pathway have been implicated in the leukemic transformation process. However, c-jun expression and the role of the JNK signaling pathway have not been investigated in primary acute myeloid leukemia (AML) cells with frequently observed balanced rearrangements such as t(8;21). In the present study, we report elevated c-jun mRNA expression in AML patient bone marrow cells with t(8;21), t(15;17) or inv(16), and a high correlation in mRNA expression levels of AML1-ETO and c-jun within t(8;21)-positive AML patient cells. In myeloid U937 cells, c-jun mRNA and protein expression increase upon inducible expression of AML1-ETO. AML1-ETO transactivates the human c-jun promoter through the proximal activator protein (AP-1) site by activating the JNK pathway. Overexpression of JNK-inhibitor JIP-1 and chemical JNK inhibitors reduce the transactivation capacity of AML1-ETO on the c-jun promoter and the proapoptotic function of AML1-ETO in U937 cells. An autocrine mechanism involving granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor (G-CSF-R) might participate in AML1-ETO mediated JNK-signaling, because AML1-ETO induces G-CSF and G-CSF-R expression, and G-CSF-R-neutralizing antibodies reduce AML1-ETO-induced JNK phosphorylation. These data suggest a model in which AML1-ETO induces proto-oncogene c-jun expression via the proximal AP-1 site of the c-jun promoter in a JNK-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromosomes, Human, Pair 21*
  • Chromosomes, Human, Pair 8*
  • Core Binding Factor Alpha 2 Subunit
  • Genes, jun*
  • Granulocyte Colony-Stimulating Factor / physiology
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Leukemia, Myeloid, Acute / genetics*
  • Mitogen-Activated Protein Kinases / physiology*
  • Oncogene Proteins, Fusion / genetics*
  • Phosphorylation
  • Promoter Regions, Genetic*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-jun / genetics*
  • RUNX1 Translocation Partner 1 Protein
  • Signal Transduction
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / genetics*
  • Transcriptional Activation
  • Translocation, Genetic*
  • U937 Cells

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • MAS1 protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-jun
  • RUNX1 Translocation Partner 1 Protein
  • Transcription Factor AP-1
  • Transcription Factors
  • Granulocyte Colony-Stimulating Factor
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases