Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia.
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.
Kronenwett
Ralf
R
Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. kronenwett@med.uni-duesseldorf.de
Butterweck
Ulf
U
Steidl
Ulrich
U
Kliszewski
Slawomir
S
Neumann
Frank
F
Bork
Simone
S
Blanco
Elena Diaz
ED
Roes
Nicole
N
Gräf
Thorsten
T
Brors
Benedikt
B
Eils
Roland
R
Maercker
Christian
C
Kobbe
Guido
G
Gattermann
Norbert
N
Haas
Rainer
R
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
D018952:Antigens, CD34; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D043562:Receptors, G-Protein-Coupled