Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

Park, E.; Gang, E. J.; Hsieh, Y. T.; Schaefer, P.; Chae, S.; Klemm, L.; Huantes, S.; Loh, M.; Conway, E. M.; Kang, E. S.; Hoe Koo, H.; Hofmann, W. K.; Heisterkamp, N.; Pelus, L.; Keerthivasan, G.; Crispino, J.; Kahn, M.; Muschen, M.; Kim, Y. M.

Blood. 2011 Jul 1; 118(8):2191-9

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.

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