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

Oncogene volume 24, pages 5313–5324 (2005)Cite this article

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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Acknowledgements

We thank Baerbel Junge, Anke Boeckmann, Hildegard Gaussmann, Sabrina Pechtel, Monika Pooten, and Elke Rosenbaum-Koenig for expert technical support. This work was financially supported by Leukaemie Liga e.V. Duesseldorf and Moonlife e.V. Karlsruhe.

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Authors and Affiliations

  1. Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Duesseldorf, Moorenstr. 5, Duesseldorf, 40225, Germany

    Ralf Kronenwett, Ulf Butterweck, Ulrich Steidl, Slawomir Kliszewski, Frank Neumann, Simone Bork, Elena Diaz Blanco, Nicole Roes, Thorsten Gräf, Guido Kobbe, Norbert Gattermann & Rainer Haas

  2. Hematology/Oncology Division, Harvard Institutes of Medicine, Boston, MA, USA

    Ulrich Steidl

  3. Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, 69120, Germany

    Benedikt Brors & Roland Eils

  4. German Resource Center for Genome Research, Heidelberg, 69120, Germany

    Christian Maercker

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  1. Ralf Kronenwett
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Correspondence to Ralf Kronenwett.

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Kronenwett, R., Butterweck, U., Steidl, U. et al. Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia. Oncogene 24, 5313–5324 (2005). https://doi.org/10.1038/sj.onc.1208596

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