title: 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.
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.
authors.affiliation: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University Munich, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Elsässer
authors.forename: Michael
authors.initials: M
authors.lastname: Franzen
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.forename: Martin
authors.initials: M
authors.lastname: Weisser
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Venkateshwar A
authors.initials: VA
authors.lastname: Reddy
authors.forename: Sebastian
authors.initials: S
authors.lastname: Burel
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
mesh_terms: D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D016758:Genes, jun; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014178:Translocation, Genetic; D020298:U937 Cells
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C000715470:MAS1 protein, human; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D000075142:RUNX1 Translocation Partner 1 Protein; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases