title: Inactivation of the p53-KLF4-CEBPA Axis in Acute Myeloid Leukemia.
abstract: OBJECTIVE
  In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved.
  
  
  METHODS
  One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines.
  
  
  RESULTS
  We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53-KLF4-CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring non-genotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells.
  
  
  CONCLUSIONS
  The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments.
authors.affiliation: Department of Clinical Research, University and University Hospital of Berne, Berne, Switzerland. Department of Medical Oncology, University and University Hospital of Berne, Berne, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Seipel
authors.affiliation: Department of Clinical Research, University and University Hospital of Berne, Berne, Switzerland.
authors.forename: Miguel Teixera
authors.initials: MT
authors.lastname: Marques
authors.affiliation: Department of Clinical Research, University and University Hospital of Berne, Berne, Switzerland.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Bozzini
authors.affiliation: Department of Clinical Research, University and University Hospital of Berne, Berne, Switzerland.
authors.forename: Christina
authors.initials: C
authors.lastname: Meinken
authors.affiliation: Department of Clinical Research, University and University Hospital of Berne, Berne, Switzerland.
authors.forename: Beatrice U
authors.initials: BU
authors.lastname: Mueller
authors.affiliation: Department of Medical Oncology, University and University Hospital of Berne, Berne, Switzerland. thomas.pabst@insel.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D060828:Induction Chemotherapy; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53