Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

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

doi:10.1182/blood-2011-04-351239

Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2191-2199
Number of pages	9
Journal	Blood
Volume	118
Issue number	8
DOIs	https://doi.org/10.1182/blood-2011-04-351239
State	Published - Aug 25 2011

ASJC Scopus subject areas

Hematology
Biochemistry
Cell Biology
Immunology

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Park, E., Gang, E. J., Hsieh, Y. T., Schaefer, P., Chae, S., Klemm, L., Huantes, S., Loh, M., Conway, E. M., Kang, E. S., Koo, H. H., Hofmann, W. K., Heisterkamp, N., Pelus, L., Keerthivasan, G., Crispino, J., Kahn, M., Müschen, M., & Kim, Y. M. (2011). Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood, 118(8), 2191-2199. https://doi.org/10.1182/blood-2011-04-351239

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title = "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.",

author = "Eugene Park and Gang, {Eun Ji} and Hsieh, {Yao Te} and Paul Schaefer and Sanna Chae and Lars Klemm and Sandra Huantes and Mignon Loh and Conway, {Edward M.} and Kang, {Eun Suk} and Koo, {Hong Hoe} and Hofmann, {Wolf Karsten} and Nora Heisterkamp and Louis Pelus and Ganesan Keerthivasan and John Crispino and Michael Kahn and Markus M{\"u}schen and Kim, {Yong Mi}",

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doi = "10.1182/blood-2011-04-351239",

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Park, E, Gang, EJ, Hsieh, YT, Schaefer, P, Chae, S, Klemm, L, Huantes, S, Loh, M, Conway, EM, Kang, ES, Koo, HH, Hofmann, WK, Heisterkamp, N, Pelus, L, Keerthivasan, G, Crispino, J, Kahn, M, Müschen, M & Kim, YM 2011, 'Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia', Blood, vol. 118, no. 8, pp. 2191-2199. https://doi.org/10.1182/blood-2011-04-351239

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AU - Park, Eugene

AU - Gang, Eun Ji

AU - Hsieh, Yao Te

AU - Schaefer, Paul

AU - Chae, Sanna

AU - Klemm, Lars

AU - Huantes, Sandra

AU - Loh, Mignon

AU - Conway, Edward M.

AU - Kang, Eun Suk

AU - Koo, Hong Hoe

AU - Hofmann, Wolf Karsten

AU - Heisterkamp, Nora

AU - Pelus, Louis

AU - Keerthivasan, Ganesan

AU - Crispino, John

AU - Kahn, Michael

AU - Müschen, Markus

AU - Kim, Yong Mi

PY - 2011/8/25

Y1 - 2011/8/25

N2 - 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.

AB - 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.

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Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

Abstract

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