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

Research output: Contribution to journalArticle

78 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 languageEnglish (US)
Pages (from-to)2191-2199
Number of pages9
JournalBlood
Volume118
Issue number8
DOIs
StatePublished - Aug 25 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    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