BCR/ABL-mediated downregulation of genes implicated in cell adhesion and motility leads to impaired migration toward CCR7 ligands CCL19 and CCL21 in primary BCR/ABL-positive cells.
The mechanism underlying p210(BCR/ABL) oncoprotein-mediated transformation in chronic myelogenous leukemia (CML) is not fully understood. We hypothesized that p210(BCR/ABL) suppresses expression of genes which may explain at least some of the pathogenetic features of CML. A subtractive cDNA library was created between BCR/ABL-enhanced-green-fluorescent-protein (GFP)-transduced umbilical cord blood (UCB) CD34+ cells and GFP-transduced UCB CD34+ cells to identify genes whose expression is downregulated by p210(BCR/ABL). At least 100 genes were identified. We have confirmed for eight of these genes that expression was suppressed by quantitative real-time-RT-PCR (Q-RT-PCR) of additional p210(BCR/ABL)-transduced CD34+ UCB cells as well as primary early chronic phase (CP) bone marrow (BM) CML CD34+ cells. Imatinib mesylate reversed downregulation of some genes, to approximately normal levels. Several of the genes are implicated in cell adhesion and motility, including L-selectin, intercellular adhesion molecule-1 (ICAM-1), and the chemokine receptor, CCR7, consistent with the known defect in adhesion and migration of CML cells. Compared with GFP UCB or normal (NL) BM CD34+ cells, p210 UCB and CML CD34+ cells migrated poorly towards the CCR7 ligands, CCL19 and CCL21, suggesting a possible role for CCR7 in the abnormal migratory behavior of CML CD34+ cells.
Jongen-Lavrencic
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Department of Medicine, University of Minnesota, Stem Cell Institute, Cancer Center, Minneapolis, MN 55455, USA.
Salesse
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Delwel
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Verfaillie
C M
CM
D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D020014:K562 Cells; D019041:L-Selectin / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology; D008024:Ligands; D012333:RNA, Messenger / Q000235:genetics; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*
C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D008024:Ligands; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D016044:Fusion Proteins, bcr-abl