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Distinct Molecular Phenotype of Malignant Cd34þ Hematopoietic

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Distinct Molecular Phenotype of Malignant Cd34þ Hematopoietic Oncogene (2005) 24, 5313–5324 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Distinct molecular phenotype of malignant CD34 þ hematopoietic stem and progenitor cells in chronic myelogenous leukemia Ralf Kronenwett*,1, Ulf Butterweck1, Ulrich Steidl1,2, Slawomir Kliszewski1, Frank Neumann1, Simone Bork1, Elena Diaz Blanco1, Nicole Roes1, Thorsten Gra¨ f1, Benedikt Brors3, Roland Eils3, Christian Maercker4, Guido Kobbe1, Norbert Gattermann1 and Rainer Haas1 1Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; 2Harvard Institutes of Medicine, Hematology/Oncology Division, Boston, MA, USA; 3Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany; 4German Resource Center for Genome Research, 69120 Heidelberg, Germany Chronic myelogenous leukemia (CML) is a malignant Keywords: CML; CD34 þ cells; gene expression; G disorder of the hematopoietic stem cell characterized by protein-coupled receptors the BCR–ABL oncogene. We examined gene expression profiles of highly enriched CD34 þ hematopoietic stem and progenitor cells from patients with CML in chronic phase using cDNA arrays covering 1.185 genes. Compar- ing CML CD34 cells with normal CD34 cells, we þ þ Introduction found 158 genes which were significantly differentially expressed. Gene expression patterns reflected BCR–ABL- Hematopoietic stem cells are characterized by the induced functional alterations such as increased cell-cycle capability of self-renewal and differentiation into the and proteasome activity. Detoxification enzymes and entire spectrum of blood cells. Knowledge gained from DNA repair proteins were downregulated in CML stem cell biology can also give novel insights into cancer CD34 cells, which might contribute to genetic instabil- þ research. Due to their life-long persistence and self- ity. Decreased expression of junction plakoglobulin and renewal capacity, stem cells have a high probability to CXC chemokine receptor 4 (CXCR-4) might facilitate the accumulate mutations that eventually result in malig- release of immature precursors from bone marrow in nant transformation. In addition, stem cells and CML. GATA-2 was upregulated in CML CD34 cells, þ malignant cells share several features such as the ability suggesting an increased self-renewal in comparison with to self-renew, similar mechanisms involved in migration normal CD34 cells. Moreover, we found upregulation þ and mechanisms for prevention of cellular aging such as of the proto-oncogene SKI and of receptors for neurome- telomerase expression (Passegue et al., 2003; Hope et al., diators such as opioid l1 receptor, GABA B receptor, 2004). adenosine A1 receptor, orexin 1 and 2 receptors and The best-studied malignant stem cell disorder is corticotropine-releasing hormone receptor. Treatment of chronic myelogenous leukemia (CML), which is char- CML progenitor cells with the selective adenosine A1 acterized by a clonal expansion of hematopoietic receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine progenitor cells (Faderl et al., 1999). In 95% of patients (DPCPX) resulted in a dose-dependent significant inhibi- a specific chromosomal translocation between chromo- tion of clonogenic growth by 40% at a concentration of somes 9 and 22 is found, which results in the formation 10À5 M, which could be reversed by the equimolar addition of the BCR–ABL fusion gene. The BCR–ABL protein of the receptor agonist 2-chloro-N6-cyclopentyladenosine has an elevated tyrosine kinase activity and plays a (P 0.05). The incubation of normal progenitor cells with o central role in the pathophysiology of the disease (Daley DPCPX resulted in an inhibition of clonogenic growth to et al., 1990; Lugo et al., 1990). Different mechanisms a significantly lesser extent in comparison with CML cells have been shown to be involved in the malignant (P 0.05), suggesting that the adenosine A1 receptor is of o transformation by BCR–ABL (Deininger et al., 2000). functional relevance in CML hematopoietic progenitor The fusion oncoprotein activates mitogenic signalling cells. pathways such as the RAS and mitogen-activated Oncogene (2005) 24, 5313–5324. doi:10.1038/sj.onc.1208596; protein kinase pathway and protects CML cells from published online 4 April 2005 apoptosis. In addition, BCR–ABL induces adhesive and cytoskeletal abnormalities, which might facilitate the release of progenitors from the bone marrow (BM). *Correspondence: R Kronenwett; E-mail: [email protected] Large-scale gene expression analyses of leukemic cells Received 2 August 2004; revised 28 January 2005; accepted 4 February from patients with Ph þ CML have been used to 2005; published online 4 April 2005 investigate a genomic profile associated with response to Molecular phenotype of CML CD34 þ cells R Kronenwett et al 5314 therapy with the tyrosine kinase inhibitor imatinib from BM or acquisition of secondary chromosomal (McLean et al., 2004) and have broadened the knowl- abnormalities resulting in transformation into blast edge about alterations of gene expression in BCR–ABL- crisis. Several genes known to increase cell-cycle positive cells in comparison with normal cells (Ohmine progression and replication such as prefoldin 4, several et al., 2001; Nowicki et al., 2003). While Ohmine and co- cyclins, cell division cycle 25C, cyclin-dependent kinase workers examined CD133 þ hematopoietic progenitor 4, interferon-inducible RNA-dependent protein kinase, cells in the study of Nowicki and co-workers mono- 14-3-3 protein beta, and telomeric repeat-binding factor nuclear CML cells were used. However, mononuclear were significantly upregulated 1.4–10-fold in CML cells are a heterogenous cell population consisting of a CD34 þ cells. On the other hand, expression of the broad spectrum of partially and completely differen- cell-cycle inhibitors cyclin-dependent kinase inhibitors tiated cell types. Therefore, the expression pattern might 1A and 2D were 2–3-fold greater in normal CD34 þ only reflect the different proportions of the leukocyte cells than in CML CD34 þ cells. subtypes in normal and CML mononuclear cells Looking at apoptosis-related genes, we found the (Szaniszlo et al., 2004). In order to compare similar cell antiapoptotic gene defender against cell death 1 to be subsets, to analyse a more homogenous cell population 2.6-fold upregulated in CML and the proapoptotic and to examine cells which are closer to the cell of origin genes caspase 2 and death-associated protein kinase 1 to in CML, we examined highly enriched CD34 þ hema- be downregulated. topoietic stem and progenitor cells. By means of cDNA Examining genes involved in adhesion, we found a array technology, hierarchical cluster analysis, quanti- heterogenous expression pattern. The two subunits of tative real-time RT–PCR, and flow cytometry, we the a4b1 integrin (VLA-4) were three-fold upregulated, identified a distinct gene expression pattern of malignant whereas the b3 integrin subunit, intercellular adhesion CD34 þ cells from patients with untreated newly molecule 1, sialophorin, and junction plakoglobin (JUP) diagnosed CML. We found numerous differentially were downregulated between 1.7- and 4.3-fold. expressed genes and demonstrated the functional role At present, the mechanisms underlying the transfor- of the adenosine A1 receptor for the clonogenic growth mation of BCR–ABL-positive cells into blast crisis are of leukemic progenitor cells. not known. A genetic instability is presumed as the basis for accumulation of mutations. Our expression data support this view since several detoxification enzymes and genes involved in DNA repair such as microsomal Results glutathione S-transferase, glutathione peroxidase 1, glutathione reductase, cytosolic superoxide dismutase, Gene expression profiles of BM-CD34 þ cells in CML mutL homolog 1, RAD23A, ATP-dependent DNA Gene expression profiles of highly enriched CD34 þ ligase 1, and the DNA excision repair proteins ERCC1, cells from the BM of five patients with untreated CML ERCC3, and ERCC5 were significantly 2–4.4-fold lower in chronic phase were compared with those of 10 healthy expressed in CML CD34 þ cells compared with normal donors (HD) using cDNA arrays covering 1185 defined CD34 þ cells. genes. A total of 158 genes of different functional groups We also found differential expression of genes which were significantly differentially expressed in CML might be suitable for targeted therapy. For example, CD34 þ cells (Po0.01), with 55 of them upregulated three proteasome subunits were 3–4-fold overexpressed and 100 downregulated in CML (Figure 1). Complete in CML, whereas the proteasome inhibitor subunit 1 expression data are shown in the Supplementary table was 1.4-fold downregulated. available at Oncogene’s website. Moreover, we found a distinct expression pattern of First, we looked at genes which are known to be growth factors, cytokines, chemokines and their recep- involved in the BCR–ABL signal transduction pathway. tors in CML CD34 þ cells. Only one was upregulated in Several proteins downstream of BCR–ABL such as CML (small inducible cytokine subfamily E1, 3.6-fold), members of the RAS family and JAK2 were 2–7-fold whereas 17 genes were significantly lower expressed in upregulated in CML. On the other hand, the serine– CML, including the cytokines and growth factors threonine kinase AKT, which is part of the BCR–ABL- macrophage colony-stimulating factor, platelet-derived activated PI3 kinase pathway, showed a 2.4-fold growth factor, and interleukin 10, as well as the reduced expression in CML CD34 þ cells. neuromedin B receptor, the granulocyte colony-stimu- In addition, the expression pattern reflected and lating factor receptor, and the CXC chemokine receptor explained the functional characteristics of CML pro- 4 (CXCR-4). genitor cells on a molecular level, such as increased Looking at genes encoding proteins involved in proliferation activity, release of immature precursors transcription, zinc-finger proteins 9, 148, and 162, Figure 1 Selection of differentially expressed genes. Results from five samples of CML CD34 þ cells (CML1-5, Table 1) and 10 samples of normal CD34 þ cells (HD1-10) are shown.
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