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Distinct Gene Expression Pattern of Malignant Hematopoietic Stem and Progenitor Cells in Polycythemia Vera
aDepartment of Hematology, Oncology, and Clinical Immunology, Heinrich Heine University, Duesseldorf, Germany bHarvard Institutes of Medicine, Boston, Massachusetts, USA cDepartment of Hematology and Oncology, Georg August University, Goettingen, Germany dDepartment of Hematology and Oncology, and Clinical Immunology, St. Johannes Hospital, Duisburg, Germany
Address for correspondence: Priv.-Doz. Dr. med. Ralf Kronenwett, Klinik für Hämatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany. Voice: +49-211-81-17720; fax: +49-211-81-18853. kronenwett{at}med.uni-duesseldorf.de
Polycythemia vera (PV) is a chronic myeloproliferative disorder with an expansion of multipotent hematopoietic progenitor cells. Although it is known that hematopoietic progenitors in PV are erythropoietin independent and hypersensitive to several cytokines, the molecular oncogenic mechanisms in PV are largely unknown. In this study, we examined gene expression profiles of CD34+ cells from bone marrow of patients with de novo PV and from healthy volunteers to identify molecular changes associated with the malignant growth of hematopoietic stem and progenitor cells in this myeloproliferative disorder. Using cDNA arrays, we found significant differences (P < .01) in the expression of 107 genes. Proapoptotic genes (CASP2, CASP3, DAPK1, ALG2) were expressed at lower levels in PV-CD34+ cells, reflecting a lower apoptotic activity. Fibrosis-stimulating growth factors (transforming growth factor ß1, transforming growth factor ß2, bone morphogenetic protein 2, and endothelial growth factor) were expressed at significantly higher levels in PV-CD34+ cells. Furthermore, PV-CD34+ cells overexpressed several receptors, protein kinases, and proteasome subunits, which might be targets for directed therapeutic approaches. It is interesting that three retinoid receptors were overexpressed in PV-CD34+ cells—retinoic acid receptor ß (RARß), retinoid X receptor ß (RXRß), and cellular retinoic acid binding protein 2 (CRABP2). Using methylcellulose colony-forming assays, we found that the formation of erythroid colonies derived from PV hematopoietic progenitors was inhibited by all-trans-retinoic acid (ATRA), a natural ligand of those receptors, in a dose-dependent manner, showing a maximum inhibition of 89% at 10 µM; the growth of myelomonocytic colonies was not significantly affected. These data suggest that the use of ATRA could be of therapeutic benefit for patients with PV.
Key Words: polycythemia vera • CD34+ cells • gene expression • detoxification enzymes • retinoid receptors • opioid µ1 receptor • proteasome
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