2′,5′-oligoadenylate-antisense chimeras cause RNase L to selectively degrade bcr/abl mRNA in chronic myelogenous leukemia cells

被引:30
作者
Maran, A
Waller, CF
Paranjape, JM
Li, GY
Xiao, W
Zhang, K
Kalaycio, ME
Maitra, RK
Lichtin, AE
Brugger, W
Torrence, PF
Silverman, RH
机构
[1] Cleveland Clin Fdn, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44195 USA
[2] Cleveland Clin Fdn, Dept Hematol & Oncol, Cleveland, OH 44195 USA
[3] NIDDKD, Sect Biomed Chem, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1182/blood.V92.11.4336.423a06_4336_4343
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We report an RNA targeting strategy, which selectively degrades bcr/abl mRNA in chronic myelogenous leukemia (CML) cells. A 2',5'-tetraadenylate activator (2-5A) of RNase L was chemically linked to oligonucleotide antisense directed against either the fusion site or against the translation start sequence in bcr/abl mRNA. Selective degradation of the targeted RNA sequences was demonstrated in assays with purified RNase L and decreases of p210(bcr/abt) kinase activity levels were obtained in the CML cell line, K562, Furthermore, the 2-5A-antisense chimeras suppressed growth of K562, while having substantially reduced effects on the promyelocytic leukemia cell line, HL60. Findings were extended to primary CML cells isolated from bone marrow of patients. The 2-5A-antisense treatments both suppressed proliferation of the leukemia cells and selectively depleted levels of bcr/abl mRNA without affecting levels of beta-actin mRNA, determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The specificity of this approach was further shown with control oligonucleotides, such as chimeras containing an inactive dimeric form of 2-5A, antisense lacking 2-5A, or chimeras with altered sequences including several mismatched nucleotides. The control oligonucleotides had either reduced or no effect on CML cell growth and bcr/abl mRNA levels. These findings show that CML cell growth can be selectively suppressed by targeting bcr/abl mRNA with 2-5A-antisense for decay by RNase L and suggest that these compounds should be further explored for their potential as ex vivo purging agents of autologous hematopoietic stem cell transplants from CML patients. (C) 1998 by The American Society of Hematology.
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页码:4336 / 4343
页数:8
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