| Abstract: |
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 a (RARα). It is suggested that the PML/RARa 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 RARα 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 RARα portion of the fusion transcript Using a full-length PML/RARα RNA or an RNA corresponding to 788 nucleotides of the PML/RARα mRNA and a full-length RARα RNA or an RNA corresponding to 960 nucleotides of the RARα 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/RARa. It is hypothesized that ribozyme-mediated inactivation of PML/RARα provides a new approach to study the role of PML/RARα in the deregulated growth and RA response of acute promyelocytic leukemia. © 1994, American Association for Cancer Research. All rights reserved. |
| Keywords: |
sequence analysis; allele; transcription factors; leukemia, promyelocytic, acute; gene rearrangement; protein processing; molecular sequence data; rna, messenger; nucleotide sequence; acute myeloblastic leukemia; gene fusion; growth regulation; base sequence; tumor growth; enzyme specificity; enzyme substrate complex; retinoic acid; protein structure, secondary; rna transcription; chromosomes, human, pair 17; chromosomes, human, pair 15; retinoic acid receptor; receptors, retinoic acid; ribozyme; rna, catalytic; human; priority journal; article; chromosome translocation 15; support, u.s. gov't, p.h.s.; translocation (genetics)
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