Abstract
Relapse of drug-resistant acute lymphoblastic leukemia (ALL) has been associated with increased expression of survivin/BIRC5, an inhibitor of apoptosis protein, suggesting a survival advantage for ALL cells. In the present study, we report that inhibition of survivin in patient-derived ALL can eradicate leukemia. Targeting survivin with shRNA in combination with chemotherapy resulted in no detectable minimal residual disease in a xenograft model of primary ALL. Similarly, pharmacologic knock-down of survivin using EZN-3042, a novel locked nucleic acid antisense oligonucleotide, in combination with chemotherapy eliminated drug-resistant ALL cells. These findings show the importance of survivin expression in drug resistance and demonstrate that survivin inhibition may represent a powerful approach to overcoming drug resistance and preventing relapse in patients with ALL.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Combined Modality Therapy
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Drug Resistance, Neoplasm / genetics
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Gene Expression
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Gene Targeting
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / deficiency
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Inhibitor of Apoptosis Proteins / genetics*
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Neoplasm, Residual
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Oligonucleotides / genetics
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Oligonucleotides / therapeutic use
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy*
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RNA, Small Interfering / genetics
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Repressor Proteins / deficiency
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Repressor Proteins / genetics
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Survivin
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Tumor Stem Cell Assay
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Xenograft Model Antitumor Assays
Substances
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BIRC5 protein, human
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Birc5 protein, mouse
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EZN 3042
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Inhibitor of Apoptosis Proteins
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Oligonucleotides
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RNA, Small Interfering
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Repressor Proteins
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Survivin