@article{Carmen P. Montano-Almendras_Ahmed Essaghir_Hélène Schoemans_Inci Varis_Laura A. Noël_Amélie I. Velghe_Dominique Latinne_Laurent Knoops_Jean-Baptiste Demoulin_2012, place={Pavia, Italy}, title={ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-κB}, volume={97}, url={https://haematologica.org/article/view/6351}, DOI={10.3324/haematol.2011.047530}, abstractNote={<strong>Background</strong> <em>ETV6-PDGFRB</em> (also called <em>TEL-PDGFRB</em>) and <em>FIP1L1-PDGFRA</em> 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.<strong>Design and Methods</strong> We introduced <em>ETV6-PDGFRB</em> and <em>FIP1L1-PDGFRA</em> into human CD34<sup>+</sup> hematopoietic progenitor and stem cells isolated from umbilical cord blood.<strong>Results</strong> 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 <em>ETV6-PDGFRB</em> and <em>FIP1L1-PDGFRA</em>. 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 <em>FIP1L1-PDGFRA</em>-positive leukemia cell line EOL1, the proliferation of which was blocked by borte-zomib 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 <em>ETV6-PDGFRB</em>. In addition, several potential regulators of this process, including HES6, MYC and FOXO3 were identified using expression microarrays.<strong>Conclusions</strong> We show that human CD34<sup>+</sup> cells expressing <em>PDGFR</em> 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 <em>PDGFR</em&gt; mutations.}, number={7}, journal={Haematologica}, author={Carmen P. Montano-Almendras and Ahmed Essaghir and Hélène Schoemans and Inci Varis and Laura A. Noël and Amélie I. Velghe and Dominique Latinne and Laurent Knoops and Jean-Baptiste Demoulin}, year={2012}, month={Jul.}, pages={1064-1072} }