Author:

Keywords:

PDGF receptor, eosinophils, hematopoietic progenitors, myeloproliferative neoplasms, signal transduction, tyrosine kinase inhibitors, Science & Technology, Life Sciences & Biomedicine, Hematology, CHRONIC MYELOMONOCYTIC LEUKEMIA, SMOOTH-MUSCLE-CELLS, TEL/PDGF-BETA-R, TEL-PDGFR-BETA, GENE, FUSION, GROWTH, ACTIVATION, EXPRESSION, KINASE, Antigens, CD34, Cell Differentiation, Cell Proliferation, Cells, Cultured, Eosinophilia, Eosinophils, Fetal Blood, Gene Expression, Hematopoietic Stem Cells, Humans, I-kappa B Kinase, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, NF-kappa B, Oncogene Proteins, Fusion, Protein Kinase Inhibitors, Receptor, Platelet-Derived Growth Factor alpha, STAT Transcription Factors, Signal Transduction, Transduction, Genetic, Transgenes, mRNA Cleavage and Polyadenylation Factors, 1102 Cardiorespiratory Medicine and Haematology, Immunology, 3201 Cardiovascular medicine and haematology

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. DESIGN AND 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.