ABSTRACT
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.
Subject(s)
Chemokine CXCL12/antagonists & inhibitors , Fusion Proteins, bcr-abl/antagonists & inhibitors , Heterocyclic Compounds/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Neoplasm Proteins/antagonists & inhibitors , Receptors, CXCR4/antagonists & inhibitors , Animals , Benzamides , Benzylamines , Cell Adhesion/drug effects , Cell Line/drug effects , Cell Line, Tumor/drug effects , Cell Line, Tumor/enzymology , Cell Line, Tumor/pathology , Coculture Techniques , Cyclams , Drug Resistance, Neoplasm/drug effects , Heterocyclic Compounds/pharmacology , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Mice , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptors, CXCR4/biosynthesis , Receptors, CXCR4/chemistry , Receptors, CXCR4/genetics , Stromal Cells/cytologyABSTRACT
In this study, we analyzed whether retroviral integration sites in repopulating hematopoietic cells correlate with genes expressed in fractions enriched in hematopoietic stem cells (HSCs). We have previously described microarray studies of two populations enriched in HSCs: CD34+/CD38- and the slow dividing fraction of CD34+/CD38- cells (SDF). Furthermore, we demonstrated that oncoretroviral integrations in severe combined immunodeficient repopulating cells are preferentially located near the transcription start. Here, we have identified 117 corresponding cDNA clones on our micro-array representing genes with retroviral integration sites. These genes revealed a higher mean signal intensity in comparison with either all genes on the array or a subset of control genes with retroviral integrations in HeLa cells. Furthermore, these genes demonstrated a higher expression in CD34+/CD38- cells and SDF. The association of gene expression and retrovirally targeted genes observed here will help to elucidate the molecular characteristics of primitive repopulating hematopoietic cells.
