ETV6-PDGFRB and FIP1l1-PDGFRA stimulate human hematopoietic progenitor proliferation and differentiation into eosinophils via NF-kB

Demoulin, Jean Baptiste;Montano Almendras, Carmen Patricia;Essaghir, Ahmed;Schoemans, Hélène;Knoops, Laurent;et.al.
(2011) ISEH 40th Annual Scientific Meeting of the Society-for-Hematology-and-Stem-Cells , AUG 25-28, 2011 — Location: Vancouver, CANADA (25.August.2011)

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  • Demoulin, Jean Baptisteorcid-logoUCLouvain
    Author
  • Montano Almendras, Carmen PatriciaUCLouvain
    Author
  • Essaghir, AhmedUCLouvain
    Author
  • Schoemans, HélèneKUL
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  • Varis, InciUCLouvain
    Author
  • Latinne, DominiqueUCLouvain
    Author
  • Knoops, Laurentorcid-logoUCLouvain
    Author
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Abstract
Receptor-tyrosine kinase fusion genes, such as ETV6-PDGFRB (also called TEL-PDGFRβ) and FIP1L1-PDGFRA, are responsible for rare chronic myeloid malignancies associated with hypereosinophilia. In mice, these oncogenes induce a myeloproliferative disorder but no eosinophilia. To gain insight into the mechanisms whereby these fusion genes affect human hematopoietic cells and in particular the eosinophil lineage, we introduced ETV6-PDGFRB and FIP1L1-PDGFRA in human CD34+ hematopoietic progenitor cells isolated from cord blood. 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 PDGF receptor fusion genes. We next showed that both fusion genes activated the transcription factors STAT1, STAT3, STAT5 and NF-κB. Phosphatidylinositol-3 kinase inhibition blocked NF-κB activation in transduced progenitors and patient cells. A mutant IκB that prevents NF-κB nuclear translocation inhibited cell growth and the expression of eosinophil markers in cells transduced with ETV6-PDGFRB. In addition, several potential regulators of this process were identified using expression microarrays. In conclusion, human CD34+ cells expressing PDGF receptor fusion oncogenes proliferate autonomously and differentiate into eosinophils in a process that requires NF-κB. These results suggest new treatment possibilities for imatinib-resistant myeloid neoplasms associated with PDGF receptor mutations.
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Demoulin, J. B., Montano Almendras, C. P., Essaghir, A., Schoemans, H., Varis, I., Latinne, D., & Knoops, L. (2011). ETV6-PDGFRB and FIP1l1-PDGFRA stimulate human hematopoietic progenitor proliferation and differentiation into eosinophils via NF-kB. Experimental Hematology, 39(8), S20. https://hdl.handle.net/2078.5/198956 (Original work published 2011)