Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to Imatinib and Nilotinib.

Despite Imatinib's remarkable success in chronic myelogenous leukemia treatment, monotherapy frequently causes resistance, underlining the rationale for combination chemotherapy. A potential approach would be interrupting the SDF-1/CXCR4 axis using the selective CXCR4 antagonist Plerixafor (previously AMD3100), as this axis has been reported to provide survival-enhancing effects to myeloid progenitor cells. By efficient CXCR4 blocking in the CXCR4(+)/BCR-ABL(+) cell line BV-173, plerixafor (1-100 muM) significantly inhibits SDF-1alpha-mediated chemotaxis and cell migration toward the murine stroma cell line FBMD-1. Furthermore, plerixafor also significantly (10-100 muM) increased the detachment rate of SDF-1-mediated/VCAM-1-associated cell adherence under shear stress. Using a stroma-dependent coculture assay, plerixafor sensitized BCR-ABL(+) cells toward tyrosine kinase inhibitor therapy. Because the level of cell killing nearly reached that of samples cultured without stroma, a cell-cell interaction disruption seems to improve the efficacy of BCR-ABL-targeting drugs. In addition, we could show that exposure of BCR-ABL(+) cells to Imatinib or Nilotinib induced an increase in surface CXCR4 expression. Our data suggest that for BCR-ABL(+) leukemia, the selective blocking of the SDF-1/CXCR4 axis by plerixafor is a potential mechanism to overcome the protective effect of the bone marrow environment, thereby increasing the therapeutic potency of anti-BCR-ABL drugs and the therapeutic window.