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 realtime-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.