TY - JOUR
T1 - Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia
AU - Kronenwett, Ralf
AU - Butterweck, Ulf
AU - Steidl, Ulrich
AU - Kliszewski, Slawomir
AU - Neumann, Frank
AU - Bork, Simone
AU - Blanco, Elena Diaz
AU - Roes, Nicole
AU - Gräf, Thorsten
AU - Brors, Benedikt
AU - Eils, Roland
AU - Maercker, Christian
AU - Kobbe, Guido
AU - Gattermann, Norbert
AU - Haas, Rainer
PY - 2005/8/11
Y1 - 2005/8/11
N2 - 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.
AB - 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.
KW - CD34+ cells
KW - CML
KW - G protein-coupled receptors
KW - Gene expression
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U2 - 10.1038/sj.onc.1208596
DO - 10.1038/sj.onc.1208596
M3 - Article
C2 - 15806158
AN - SCOPUS:24044542316
SN - 0950-9232
VL - 24
SP - 5313
EP - 5324
JO - Oncogene
JF - Oncogene
IS - 34
ER -