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A Ribozyme Which Discriminates in Vitro between PML/RAR, the t(15;17)-associated Fusion RNA of Acute Promyelocytic Leukemia, and PML and RAR, the Transcripts from the Nonrearranged Alleles¹

Innovir Laboratories, Inc., New York, New York 10021 [U. P., J. M. B., B. J. M., A. R. G.]; Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Hospital, New York, New York 10021 [W. H. M., E. D.]; and Molecular Pharmacology and Therapeutics Program, Sloan-Kettering Institute, Memorial-Sloan Kettering Cancer Center, New York, New York 10021 [E. D.]

Acute promyelocytic leukemia (FAB M3) is distinguished by the presence of the t(15;17) and clinical response to all-trans retinoic acid (RA) treatment. Acute promyelocytic leukemia is associated with a chromosomal translocation which results in the fusion of genes encoding a putative transcription factor (PML) and the retinoic acid receptor (RAR). It is suggested that the PML/RAR fusion protein functions as an inhibitor of myeloid differentiation. The potential use of ribozymes as therapeutic agents has been investigated in the present study. Hammerhead ribozymes, which by hybridizing to both PML and RAR sequences discriminate between the fusion transcript and the normal transcripts from the nonrearranged alleles, were designed and synthesized. Two hammerhead cleavage sites were targeted: site 1, an AUU located 4 nucleotides 3' to the fusion junction; and site 2, a UUC located 26 nucleotides 3' to the junction. Both sites are located in the RAR portion of the fusion transcript. Using a full-length PML/RAR RNA or an RNA corresponding to 788 nucleotides of the PML/RAR mRNA and a full-length RAR RNA or an RNA corresponding to 960 nucleotides of the RAR mRNA as model substrates, the catalytic behavior of several ribozymes was studied. A modified hammerhead directed against site 2 displayed the highest degree of selectivity for PML/RAR. It is hypothesized that ribozyme-mediated inactivation of PML/RAR provides a new approach to study the role of PML/RAR in the deregulated growth and RA response of acute promyelocytic leukemia.

¹ This work was supported in part by NIH Grant RO1 CA 62275-01.

² To whom requests for reprints should be addressed, at Innovir Laboratories, Inc., 510 East 73rd Street, New York, NY 10021.

Received 3/15/94. Accepted 11/ 3/94.

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