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 þ hematopoietic stem and progenitor cells from patients with CML in chronic phase using cDNA arrays covering 1.185 genes. Comparing CML CD34 þ cells with normal CD34 þ cells, we found 158 genes which were significantly differentially expressed. Gene expression patterns reflected BCR-ABLinduced functional alterations such as increased cell-cycle and proteasome activity. Detoxification enzymes and DNA repair proteins were downregulated in CML CD34 þ 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 þ cells, suggesting an increased self-renewal in comparison with normal CD34 þ cells. Moreover, we found upregulation of the proto-oncogene SKI and of receptors for neuromediators such as opioid l1 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 À5 M, which could be reversed by the equimolar addition of the receptor agonist 2-chloro-N6-cyclopentyladenosine (Po0.05). 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 (Po0.05), suggesting that the adenosine A1 receptor is of functional relevance in CML hematopoietic progenitor cells.

Deregulated TGF-β signaling in leukemogenesis

“…Previous studies have found that numerous TGF-b negative regulators are overexpressed in some subsets of (Dahl et al, 1998;Kronenwett et al, 2005). c-Ski oncoproteins negatively regulate TGF-b signaling through their ability to interfere with the formation of the R-Smad and Smad4 complex and by recruiting transcription corepressors (N-CoR) and histone deacetylase (HDAC) (Liu et al, 2001).…”

Insights into the stem cells of chronic myeloid leukemia

“…These have reinforced early evidence of activation of the JAK/STAT, PI3K/ AKT, RAS/MAPK and NFkB pathways in the primitive CML cells. [115][116][117][118][119][120][121][122] These studies have also identified differentially expressed genes involved in the regulation of DNA repair, cell cycle control, cell adhesion, homing, transcription factors and drug metabolism. 117,[120][121][122][123] Potential new therapeutic targets include several recently identified regulators of CML stem and progenitor self-renewal and proliferation; for example, promyelocytic leukemia protein, b-catenin, various RNA binding proteins and members of the sonic hedgehog pathway.…”

“…[115][116][117][118][119][120][121][122] These studies have also identified differentially expressed genes involved in the regulation of DNA repair, cell cycle control, cell adhesion, homing, transcription factors and drug metabolism. 117,[120][121][122][123] Potential new therapeutic targets include several recently identified regulators of CML stem and progenitor self-renewal and proliferation; for example, promyelocytic leukemia protein, b-catenin, various RNA binding proteins and members of the sonic hedgehog pathway. [89][90][91]97,124,125 Another candidate target identified is CXCR4, the chemokine receptor thought to be involved in normal stem cell localization in the marrow and found to promote the survival of quiescent CML progenitors.…”

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

“…Given that Ski can strongly influence the biological role of PU.1, Ski might also be involved in the cell fate determination and leukemogenesis. Recently, we and others reported that Ski expression is highly upregulated in bone marrow samples from patients with monosomy 7 or deletion 7q acute myeloid leukemia (AML) and CD34 þ cells from patients with chronic myelogenous leukemia (CML) (Kronenwett et al, 2005;Ritter et al, 2006). The effect of Ski on PU.1 might render Ski a more potent inhibitor of cell differentiation in cooperation with its known repression activity in retinoic acid signaling in myeloid cells (Dahl et al, 1998;Ritter et al, 2006).…”

“…Analyses of human tumors have accumulated evidence that Ski is overexpressed in certain types of tumors such as leukemias, melanomas and esophageal carcinomas (Reed et al, 2001;Fukuchi et al, 2004;Kronenwett et al, 2005;Ritter et al, 2006). Ski has been also shown to influence the growth and differentiation of hematopoietic cells (Larsen et al, 1992(Larsen et al, , 1993Beug et al, 1995;Dahl et al, 1998).…”