title: ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-κB.
abstract: BACKGROUND
  ETV6-PDGFRB (also called TEL-PDGFRB) and FIP1L1-PDGFRA are receptor-tyrosine kinase fusion genes that cause chronic myeloid malignancies associated with hypereosinophilia. The aim of this work was to gain insight into the mechanisms whereby fusion genes affect human hematopoietic cells and in particular the eosinophil lineage.
  
  
  METHODS
  We introduced ETV6-PDGFRB and FIP1L1-PDGFRA into human CD34(+) hematopoietic progenitor and stem cells isolated from umbilical cord blood.
  
  
  RESULTS
  Cells transduced with these oncogenes formed hematopoietic colonies even in the absence of cytokines. Both oncogenes also stimulated the proliferation of cells in liquid culture and their differentiation into eosinophils. This model thus recapitulated key features of the myeloid neoplasms induced by ETV6-PDGFRB and FIP1L1-PDGFRA. We next showed that both fusion genes activated the transcription factors STAT1, STAT3, STAT5 and nuclear factor-κB. Phosphatidylinositol-3 kinase inhibition blocked nuclear factor-κB activation in transduced progenitor cells and patients' cells. Nuclear factor-κB was also activated in the human FIP1L1-PDGFRA-positive leukemia cell line EOL1, the proliferation of which was blocked by bortezomib and the IκB kinase inhibitor BMS-345541. A mutant IκB that prevents nuclear translocation of nuclear factor-κB inhibited cell growth and the expression of eosinophil markers, such as the interleukin-5 receptor and eosinophil peroxidase, in progenitors transduced with ETV6-PDGFRB. In addition, several potential regulators of this process, including HES6, MYC and FOXO3 were identified using expression microarrays.
  
  
  CONCLUSIONS
  We show that human CD34(+) cells expressing PDGFR fusion oncogenes proliferate autonomously and differentiate towards the eosinophil lineage in a process that requires nuclear factor-κB. These results suggest new treatment possibilities for imatinib-resistant myeloid neoplasms associated with PDGFR mutations.
authors.affiliation: Université catholique de Louvain, de Duve Institute, avenue Hippocrate 75, BE-1200 Brussels, Belgium.
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Montano-Almendras
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essaghir
authors.forename: Hélène
authors.initials: H
authors.lastname: Schoemans
authors.forename: Inci
authors.initials: I
authors.lastname: Varis
authors.forename: Laura A
authors.initials: LA
authors.lastname: Noël
authors.forename: Amélie I
authors.initials: AI
authors.lastname: Velghe
authors.forename: Dominique
authors.initials: D
authors.lastname: Latinne
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004802:Eosinophilia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005312:Fetal Blood; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014161:Transduction, Genetic; D019076:Transgenes; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D018952:Antigens, CD34; D051550:I-kappa B Kinase; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D050791:STAT Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors; C464679:ETV6-PDGFRB fusion protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D000097764:ETS Translocation Variant 6 Protein; C479819:FIP1L1-PDGFRA fusion protein, human