Notch1 produces a deregulation of Chemochine receptors expression in leukemic cells

Tumor cells often express deregulated profiles of chemokine receptors (CRs) which critically regulate cancer cell migration and growth. We postulated that the oncogenic transformation itself would affect CRs expression. To address this issue we studied the effects of the Notch1 oncogene on the expression of a number of CRs, namely CCR5, CCR8, CCR9, CXCR4 and CXCR6, in a panel of T-ALL cell lines. Variations of Notch activity, obtained by treatment with gamma-secretase inhibitor (5-25 microM DAPT), displayed that mRNA and protein expression of all analyzed CRs was dependent upon Notch activity, with the exception of CXCR4. Functional consequences of Notch inhibition were analyzed for CCR5 and CCR9 and CXCR4: DAPT inhibits chemotaxis induced by CCL25, ligand of CCR9, and by MIP-1beta ligand of CCR5, but leaved unaltered cell response to CXCR4 ligand, SDF-1. Moreover, CCR9 engagement was able to reduce inhibition of cell proliferation induced by DAPT in GSI-sensitive cell lines (T-ALL and DND41). RNA interference for Notch1 on Jurkat cells allowed us to show the specific contribution of this isoforms in the regulation of CCR5 and CCR9 expression and functions. The contribution of a notable Notch target, c-Myc, in CRs regulation was investigated. Inhibition of c-Myc activity, obtained by 100 microM 10058-F4 for 24h, or c-Myc forced expression in Jurkat cells pointed out c-Myc involvement in CRs expression. These results suggest that the integrated activities of Notch and c-Myc may have a role in determining CRs deregulation in leukemic cells.