Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia

Ralf Kronenwett, Ulf Butterweck, Ulrich G. Steidl, Slawomir Kliszewski, Frank Neumann, Simone Bork, Elena Diaz Blanco, Nicole Roes, Thorsten Gräf, Benedikt Brors, Roland Eils, Christian Maercker, Guido Kobbe, Norbert Gattermann, Rainer Haas

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Chronic myelogenous leukemia (CML) is a malignant disorder of the hematopoietic stem cell characterized by the BCR-ABL oncogene. We examined gene expression profiles of highly enriched CD34+ hematopoietic stem and progenitor cells from patients with CML in chronic phase using cDNA arrays covering 1.185 genes. Comparing CML CD34+ cells with normal CD34+ cells, we found 158 genes which were significantly differentially expressed. Gene expression patterns reflected BCR-ABL-induced functional alterations such as increased cell-cycle and proteasome activity. Detoxification enzymes and DNA repair proteins were downregulated in CML CD34+ cells, which might contribute to genetic instability. Decreased expression of junction plakoglobulin and CXC chemokine receptor 4 (CXCR-4) might facilitate the release of immature precursors from bone marrow in CML. GATA-2 was upregulated in CML CD34+ cells, suggesting an increased self-renewal in comparison with normal CD34+ cells. Moreover, we found upregulation of the proto-oncogene SKI and of receptors for neuromediators such as opioid μ1 receptor, GABA B receptor, adenosine A1 receptor, orexin 1 and 2 receptors and corticotropine-releasing hormone receptor. Treatment of CML progenitor cells with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) resulted in a dose-dependent significant inhibition of clonogenic growth by 40% at a concentration of 10 -5 M, which could be reversed by the equimolar addition of the receptor agonist 2-chloro-N6-cyclopentyladenosine (P < 0.05). The incubation of normal progenitor cells with DPCPX resulted in an inhibition of clonogenic growth to a significantly lesser extent in comparison with CML cells (P < 0.05), suggesting that the adenosine A1 receptor is of functional relevance in CML hematopoietic progenitor cells.

Original languageEnglish (US)
Pages (from-to)5313-5324
Number of pages12
JournalOncogene
Volume24
Issue number34
DOIs
StatePublished - Aug 11 2005
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hematopoietic Stem Cells
Phenotype
Adenosine A1 Receptors
Stem Cells
Orexin Receptors
Adenosine A1 Receptor Antagonists
CXCR4 Receptors
DNA Repair Enzymes
GABA-B Receptors
Leukemia, Myeloid, Chronic Phase
Neurotransmitter Receptor
Proto-Oncogenes
Opioid Receptors
Proteasome Endopeptidase Complex
Growth
Oligonucleotide Array Sequence Analysis
Oncogenes
Transcriptome
Genes

Keywords

  • CD34+ cells
  • CML
  • G protein-coupled receptors
  • Gene expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia. / Kronenwett, Ralf; Butterweck, Ulf; Steidl, Ulrich G.; Kliszewski, Slawomir; Neumann, Frank; Bork, Simone; Blanco, Elena Diaz; Roes, Nicole; Gräf, Thorsten; Brors, Benedikt; Eils, Roland; Maercker, Christian; Kobbe, Guido; Gattermann, Norbert; Haas, Rainer.

In: Oncogene, Vol. 24, No. 34, 11.08.2005, p. 5313-5324.

Research output: Contribution to journalArticle

Kronenwett, R, Butterweck, U, Steidl, UG, Kliszewski, S, Neumann, F, Bork, S, Blanco, ED, Roes, N, Gräf, T, Brors, B, Eils, R, Maercker, C, Kobbe, G, Gattermann, N & Haas, R 2005, 'Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia', Oncogene, vol. 24, no. 34, pp. 5313-5324. https://doi.org/10.1038/sj.onc.1208596
Kronenwett, Ralf ; Butterweck, Ulf ; Steidl, Ulrich G. ; Kliszewski, Slawomir ; Neumann, Frank ; Bork, Simone ; Blanco, Elena Diaz ; Roes, Nicole ; Gräf, Thorsten ; Brors, Benedikt ; Eils, Roland ; Maercker, Christian ; Kobbe, Guido ; Gattermann, Norbert ; Haas, Rainer. / Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia. In: Oncogene. 2005 ; Vol. 24, No. 34. pp. 5313-5324.
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abstract = "Chronic myelogenous leukemia (CML) is a malignant disorder of the hematopoietic stem cell characterized by the BCR-ABL oncogene. We examined gene expression profiles of highly enriched CD34+ hematopoietic stem and progenitor cells from patients with CML in chronic phase using cDNA arrays covering 1.185 genes. Comparing CML CD34+ cells with normal CD34+ cells, we found 158 genes which were significantly differentially expressed. Gene expression patterns reflected BCR-ABL-induced functional alterations such as increased cell-cycle and proteasome activity. Detoxification enzymes and DNA repair proteins were downregulated in CML CD34+ cells, which might contribute to genetic instability. Decreased expression of junction plakoglobulin and CXC chemokine receptor 4 (CXCR-4) might facilitate the release of immature precursors from bone marrow in CML. GATA-2 was upregulated in CML CD34+ cells, suggesting an increased self-renewal in comparison with normal CD34+ cells. Moreover, we found upregulation of the proto-oncogene SKI and of receptors for neuromediators such as opioid μ1 receptor, GABA B receptor, adenosine A1 receptor, orexin 1 and 2 receptors and corticotropine-releasing hormone receptor. Treatment of CML progenitor cells with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) resulted in a dose-dependent significant inhibition of clonogenic growth by 40{\%} at a concentration of 10 -5 M, which could be reversed by the equimolar addition of the receptor agonist 2-chloro-N6-cyclopentyladenosine (P < 0.05). The incubation of normal progenitor cells with DPCPX resulted in an inhibition of clonogenic growth to a significantly lesser extent in comparison with CML cells (P < 0.05), suggesting that the adenosine A1 receptor is of functional relevance in CML hematopoietic progenitor cells.",
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AU - Kliszewski, Slawomir

AU - Neumann, Frank

AU - Bork, Simone

AU - Blanco, Elena Diaz

AU - Roes, Nicole

AU - Gräf, Thorsten

AU - Brors, Benedikt

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