INHIBITION OF BCR-ABL EXPRESSION WITH ANTISENSE OLIGODEOXYNUCLEOTIDESRESTORES BETA-1 INTEGRIN-MEDIATED ADHESION AND PROLIFERATION INHIBITION IN CHRONIC MYELOGENOUS LEUKEMIA HEMATOPOIETIC PROGENITORS

Chronic myelogenous leukemia (CML) is characterized by the continuous proliferation and abnormal circulation of malignant hematopoietic prog enitors, This may he related to the unresponsiveness of CML progenitor s to beta 1 integrin adhesion receptor-mediated inhibition of progenit or proliferation by the marrow microenvironment. In hematopoietic cell lines, the BCR-ABL oncogene product, p210(BCR-ABL), interacts with a variety of cytoskeletal elements important for normal integrin signali ng. We studied the role of p210(BCR-ABL) in abnormal integrin function in CML by evaluating the effect of inhibition of BCR-ABL expression w ith antisense oligodeoxynucleotides (AS-ODNs) on integrin-mediated adh esion and proliferation inhibition of malignant primary progenitors fr om CML marrow, Preincubation of CML CD34(+)HLA-DR+ (DR+) cells with br eakpoint-specific AS-ODNs significantly increased adhesion of CML prog enitors to stroma and fibronectin (FN), Pretreatment with breakpoint-s pecific ODNs also resulted in significant inhibition of CML progenitor proliferation after ligand or antibody-mediated beta 1 integrin engag ement. Breakpoint-specific ODNs were significantly more effective in r estoring CML progenitor adhesion and proliferation inhibition than con trol ODNs, BCR-ABL mRNA and p210(BCR-ABL) levels in CML CD34(+) cells were significantly reduced after incubation with breakpoint-specific A S-ODN, These studies indicate a role for BCR ABL in abnormal circulati on and defective integrin-dependent microenvironmental regulation of p roliferation of CML hematopoietic progenitors. (C) 1998 by The America n Society of Hematology.