title: Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera.
abstract: 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 beta1, transforming growth factor beta2, 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 beta (RARbeta), retinoid X receptor beta (RXRbeta), 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 microM; 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.
authors.affiliation: Klinik für Hämatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Thomas
authors.initials: T
authors.lastname: Schroeder
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Guido
authors.initials: G
authors.lastname: Kobbe
authors.forename: Thorsten
authors.initials: T
authors.lastname: Graef
authors.forename: Simone
authors.initials: S
authors.lastname: Bork
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pechtel
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kliszewski
authors.forename: Andrea
authors.initials: A
authors.lastname: Kuendgen
authors.forename: Ulrich P
authors.initials: UP
authors.lastname: Rohr
authors.forename: Roland
authors.initials: R
authors.lastname: Fenk
authors.forename: Michael
authors.initials: M
authors.lastname: Schroeder
authors.forename: Detlef
authors.initials: D
authors.lastname: Haase
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Ralf
authors.initials: R
authors.lastname: Kronenwett
mesh_terms: D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011087:Polycythemia Vera / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology