Designing of chimeric DNA/RNA hammerhead ribozymes to be targeted against AML1/MTG8 mRNA.
For therapeutic purposes, two chimeric DNA/RNA hammerhead ribozymes were synthesized to cleave AML1/MTG8, the t(8;21)-associated fusion mRNA of acute myeloid leukemia. One ribozyme, A/MRZ-1, recognizes the area adjacent to the fusion point between AML1 and MTG8, and cleaves six bases downstream from this point. The other, MRZ-1, recognizes the MTG8 sequence. Both ribozymes cleaved synthetic chimeric DNA/RNA substrates at theoretical sites. Neither cleaved AML1 RNA. A/MRZ-1 cleaved only AML1/MTG8 RNA, and MRZ-1 cleaved both AML1/MTG8 and MTG8 RNAs. The two ribozymes showed growth inhibition of an acute myeloid leukemia cell line carrying t(8;21), SKNO-1 cells. The same extent of growth inhibition was attained by antisense oligonucleotides against AML1/MTG8 RNA. The results suggest that the ribozyme has the potential to be developed as a useful agent for gene therapy, in particular for leukemia with t(8;21).
Kozu
T
T
Department of Immunology and Virology, Saitama Cancer Center Research Institute, Japan.
Sueoka
E
E
Okabe
S
S
Sueoka
N
N
Komori
A
A
Fujiki
H
H
D000970:Antineoplastic Agents / Q000737:chemistry*; D001483:Base Sequence; D050676:Core Binding Factor Alpha 2 Subunit; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics*; D006131:Growth Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000628:therapy*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D016337:RNA, Catalytic / Q000737:chemistry / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016337:RNA, Catalytic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D004247:DNA