MULTIUNIT RIBOZYME-MEDIATED CLEAVAGE OF BCR-ABL MESSENGER-RNA IN MYELOID LEUKEMIAS

Chronic myelogenous leukemia is characterized by the Philadelphia chro mosome, which at the molecular level results from the fusion of the bc r gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity , In this study, we have synthesized a multi-unit ribozyme that target s bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cl eavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into mur ine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozym e transfection was accomplished either by liposomes or using folic aci d-polylysine as a carrier. Multi-unit ribozyme transfection reduced th e level of bcr-abl mRNA 3 logs when transfected via folate receptor-me diated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the t reatment of Philadelphia chromosome-positive chronic myelogenous leuke mia. (C) 1995 by The American Society of Hematology.