title: C/EBPβ expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway.
abstract: BACKGROUND
  Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is characterized by the t(2;5) chromosomal translocation, resulting in the expression of a fusion protein formed of nucleophosmin (NPM) and ALK. Recently, we reported the abnormal expression of the transcription factor CCAAT/enhancer binding protein-beta (C/EBPbeta) in ALK-positive anaplastic large cell lymphomas, and demonstrated its dependence on NPM-ALK activity.
  
  
  METHODS
  In this study, the role of C/EBPbeta in proliferation and survival of ALK-positive anaplastic large cell lymphomas was investigated, as well as the mechanism of its expression and activity. Highly effective short hairpin RNA sequences and/or pharmacological inhibitors were used to abrogate the expression or activity of C/EBPbeta, signal transducer and activator of transcription 3 (STAT3), AKT, extracellular signal-related kinase 1/2 (ERK1/2) and mammalian target of rapamycin (mTOR).
  
  
  RESULTS
  Interference with C/EBPbeta expression resulted in a dramatic decrease in cell proliferation in ALK-positive anaplastic large cell lymphomas, with a mild induction of apoptosis after 6 days. Down-regulation of STAT3 resulted in a marked decrease in C/EBPbeta mRNA and protein levels with impairment in cell proliferation and viability, underscoring the important role of these two proteins in ALK-mediated oncogenesis. Additionally, we demonstrated that reduction of ERK1/2 activity led to C/EBPbeta Thr(235) dephosphorylation and moderate growth retardation. The AKT/mTOR signaling pathway did not have any influence on C/EBPbeta expression or C/EBPbeta phosphorylation.
  
  
  CONCLUSIONS
  These findings reveal the convergence of STAT3 and ERK1/2 signaling pathways activated by NPM-ALK in mediating the regulation of C/EBPbeta expression, a transcription factor central to NPM-ALK transformation.
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Germany.
authors.forename: Natasa
authors.initials: N
authors.lastname: Anastasov
authors.forename: Irina
authors.initials: I
authors.lastname: Bonzheim
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.forename: Margit
authors.initials: M
authors.lastname: Klier
authors.forename: Therese
authors.initials: T
authors.lastname: Dau
authors.forename: Daniela
authors.initials: D
authors.lastname: Angermeier
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases