Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia.

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.
Authors	Eugene Park, Eun Ji Gang, Yao-Te Hsieh, Paul Schaefer, Sanna Chae, Lars Klemm, Sandra Huantes, Mignon Loh, Edward M Conway, Eun-Suk Kang, Hong Hoe Koo, Wolf-Karsten Hofmann, Nora Heisterkamp, Louis Pelus, Ganesan Keerthivasan, John Crispino, Michael Kahn, Markus Müschen, Yong-Mi Kim
Journal	Blood (Blood) Vol. 118 Issue 8 Pg. 2191-9 (Aug 25 2011) ISSN: 1528-0020 [Electronic] United States
PMID	21715311 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	BIRC5 protein, human Birc5 protein, mouse EZN 3042 Inhibitor of Apoptosis Proteins Oligonucleotides RNA, Small Interfering Repressor Proteins Survivin
Topics	Animals Combined Modality Therapy Drug Resistance, Neoplasm (genetics) Gene Expression Gene Targeting Humans Inhibitor of Apoptosis Proteins (antagonists & inhibitors, deficiency, genetics) Mice Mice, Inbred NOD Mice, Knockout Neoplasm, Residual Oligonucleotides (genetics, therapeutic use) Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, therapy) RNA, Small Interfering (genetics) Repressor Proteins (deficiency, genetics) Survivin Tumor Stem Cell Assay Xenograft Model Antitumor Assays

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