title: Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia.
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.
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. kronenwett@med.uni-duesseldorf.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Kronenwett
authors.forename: Ulf
authors.initials: U
authors.lastname: Butterweck
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kliszewski
authors.forename: Frank
authors.initials: F
authors.lastname: Neumann
authors.forename: Simone
authors.initials: S
authors.lastname: Bork
authors.forename: Elena Diaz
authors.initials: ED
authors.lastname: Blanco
authors.forename: Nicole
authors.initials: N
authors.lastname: Roes
authors.forename: Thorsten
authors.initials: T
authors.lastname: Gräf
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Christian
authors.initials: C
authors.lastname: Maercker
authors.forename: Guido
authors.initials: G
authors.lastname: Kobbe
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis*; D015536:Down-Regulation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D043562:Receptors, G-Protein-Coupled