Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera

Ulrich G. Steidl, Thomas Schroeder, Christian Steidl, Guido Kobbe, Thorsten Graef, Simone Bork, Sabrina Pechtel, Slawomir Kliszewski, Andrea Kuendgen, Ulrich P. Rohr, Roland Fenk, Michael Schroeder, Detlef Haase, Rainer Haas, Ralf Kronenwett

Research output: Contribution to journalArticle

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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 β1, transforming growth factor β2, 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 β (RARβ), retinoid X receptor β (RXRβ), 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.

Original languageEnglish (US)
Pages (from-to)94-108
Number of pages15
JournalAnnals of the New York Academy of Sciences
Volume1044
DOIs
StatePublished - 2005
Externally publishedYes

Fingerprint

Polycythemia Vera
Retinoic Acid Receptors
Transforming Growth Factors
Hematopoietic Stem Cells
Tretinoin
Gene expression
Genes
Endothelial Growth Factors
Retinoid X Receptors
Gene Expression
Bone Morphogenetic Protein 2
Methylcellulose
Retinoids
Proteasome Endopeptidase Complex
Erythropoietin
Caspase 3
Protein Kinases
Assays
Bone
Complementary DNA

Keywords

  • CD34 cells
  • Detoxification enzymes
  • Gene expression
  • Opioid μ1 receptor
  • Polycythemia vera
  • Proteasome
  • Retinoid receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera. / Steidl, Ulrich G.; Schroeder, Thomas; Steidl, Christian; Kobbe, Guido; Graef, Thorsten; Bork, Simone; Pechtel, Sabrina; Kliszewski, Slawomir; Kuendgen, Andrea; Rohr, Ulrich P.; Fenk, Roland; Schroeder, Michael; Haase, Detlef; Haas, Rainer; Kronenwett, Ralf.

In: Annals of the New York Academy of Sciences, Vol. 1044, 2005, p. 94-108.

Research output: Contribution to journalArticle

Steidl, UG, Schroeder, T, Steidl, C, Kobbe, G, Graef, T, Bork, S, Pechtel, S, Kliszewski, S, Kuendgen, A, Rohr, UP, Fenk, R, Schroeder, M, Haase, D, Haas, R & Kronenwett, R 2005, 'Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera', Annals of the New York Academy of Sciences, vol. 1044, pp. 94-108. https://doi.org/10.1196/annals.1349.013
Steidl, Ulrich G. ; Schroeder, Thomas ; Steidl, Christian ; Kobbe, Guido ; Graef, Thorsten ; Bork, Simone ; Pechtel, Sabrina ; Kliszewski, Slawomir ; Kuendgen, Andrea ; Rohr, Ulrich P. ; Fenk, Roland ; Schroeder, Michael ; Haase, Detlef ; Haas, Rainer ; Kronenwett, Ralf. / Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera. In: Annals of the New York Academy of Sciences. 2005 ; Vol. 1044. pp. 94-108.
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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 β1, transforming growth factor β2, 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 β (RARβ), retinoid X receptor β (RXRβ), 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.",
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AU - Schroeder, Thomas

AU - Steidl, Christian

AU - Kobbe, Guido

AU - Graef, Thorsten

AU - Bork, Simone

AU - Pechtel, Sabrina

AU - Kliszewski, Slawomir

AU - Kuendgen, Andrea

AU - Rohr, Ulrich P.

AU - Fenk, Roland

AU - Schroeder, Michael

AU - Haase, Detlef

AU - Haas, Rainer

AU - Kronenwett, Ralf

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