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 mu1 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.
Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. kronenwett@med.uni-duesseldorf.de
%0 Journal Article
%1 Kronenwett2005
%A Kronenwett, Ralf
%A Butterweck, Ulf
%A Steidl, Ulrich
%A Kliszewski, Slawomir
%A Neumann, Frank
%A Bork, Simone
%A Blanco, Elena Diaz
%A Roes, Nicole
%A Gräf, Thorsten
%A Brors, Benedikt
%A Eils, Roland
%A Maercker, Christian
%A Kobbe, Guido
%A Gattermann, Norbert
%A Haas, Rainer
%D 2005
%J Oncogene
%K Adult; Aged; Analysis; Antigens, Array BCR-ABL CD34, Cells, Chain Chronic, Cytometry; Down-Regulation; Expression Flow G-Protein-Coupled, Gene Hematopoietic Humans; Leukemia, Middle Myelogenous, Neoplastic; Oligonucleotide Phenotype; Polymerase Positive, Profiling; Reaction; Receptors, Regulation, Reverse Sequence Stem Transcriptase Up-Regulation analysis; biosynthesis; genetics/immunology; physiology;
%N 34
%P 5313--5324
%R 10.1038/sj.onc.1208596
%T Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia.
%U http://dx.doi.org/10.1038/sj.onc.1208596
%V 24
%X 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 mu1 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.
@article{Kronenwett2005,
__markedentry = {[bbrors:6]},
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 mu1 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.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Kronenwett, Ralf and Butterweck, Ulf and Steidl, Ulrich and Kliszewski, Slawomir and Neumann, Frank and Bork, Simone and Blanco, Elena Diaz and Roes, Nicole and Gr{\"{a}}f, Thorsten and Brors, Benedikt and Eils, Roland and Maercker, Christian and Kobbe, Guido and Gattermann, Norbert and Haas, Rainer},
biburl = {https://www.bibsonomy.org/bibtex/29eb318e945a22f817715493e3ec40188/bbrors},
doi = {10.1038/sj.onc.1208596},
institution = {Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. kronenwett@med.uni-duesseldorf.de},
interhash = {3b0635862b0fd7f0fee2dd7f9009174b},
intrahash = {9eb318e945a22f817715493e3ec40188},
journal = {Oncogene},
keywords = {Adult; Aged; Analysis; Antigens, Array BCR-ABL CD34, Cells, Chain Chronic, Cytometry; Down-Regulation; Expression Flow G-Protein-Coupled, Gene Hematopoietic Humans; Leukemia, Middle Myelogenous, Neoplastic; Oligonucleotide Phenotype; Polymerase Positive, Profiling; Reaction; Receptors, Regulation, Reverse Sequence Stem Transcriptase Up-Regulation analysis; biosynthesis; genetics/immunology; physiology;},
language = {eng},
medline-pst = {ppublish},
month = Aug,
number = 34,
owner = {bbrors},
pages = {5313--5324},
pii = {1208596},
pmid = {15806158},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia.},
url = {http://dx.doi.org/10.1038/sj.onc.1208596},
volume = 24,
year = 2005
}