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 patientderived 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 elimi- IntroductionWhereas the overall prognosis for patients with acute lymphoblastic leukemia (ALL) has improved over the past decades, with an overall survival of approximately 45%-60% for adults 1 and approximately 80% for children, 2,3 relapse of drug-resistant leukemia remains a significant problem. Although cure rates in children are high, recurrent leukemia leads to death in 50%-95% of cases depending on the site of recurrence. 4 Moreover, survivors often suffer from secondary neoplasms and chronic or late-occurring health problems. 5 Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) gene family, 6 has been shown to inhibit apoptosis, enhance proliferation and promote angiogenesis, 7,8 but an indirect association with pro-and antiapoptotic proteins has also been described. 7,9,10 Caspase-independent inhibition of cell death has been attributed to the inhibition of apoptosis-inducing factordependent apoptotic pathways, which are known to induce caspaseindependent DNA fragmentation. 11 Death of cells lacking survivin is thought to be due to incomplete mitosis. 12 Survivin is localized to the microtubules of the mitotic spindle, where it plays an essential role in maintaining high fidelity at cell-cycle checkpoints and transitions. 13 Survivin is itself up-regulated in a cell-cycledependent manner at the G 2 /M phase. 14 Survivin associates with Aurora B kinase and Borrealin to form the chromosome passenger complex that is involved in mitosis, 15 cell-cycle progression, and cytokinesis. 16 Survivin was also shown to play a role in the proliferation of leukemia that was induced by internal tandem duplication of FLT3, 17 and may promote tumorigenesis in vivo by imparting a survival advantage. 18 Survivin is selectively expressed in fetal and proliferating tissues and in various solid tumors 19 and hematologic malignancies. 20 In addition, elevated survivin expression in cancer has been associated with poor prognosis. In particular, gene-expression analysis of matched diagnosis-relapse pairs of ALL samples revealed higher expression levels of survivin at relapse than at diagnosis. 21 However, whether survivin inhibition can actually prevent relapse in primary ALL has not been examined. In the present study, we investigated the role of survivin in primary ALL and evaluated survivin as a potential target for therapy of primary ALL. Methods Patient samplesBone marrow and peripheral blood...

Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia

“…We demonstrated that expression of both of these genes could be decreased after vorinostat exposure. Improving chemosensitivity by performing knock-down experiments of BIRC5 has been shown by us 26 and others 29 and has further supported its role in chemoresistance. Similarly, down-regulation of genes such as NR3C1 and BTG1 have been linked previously to glucocorticoid resistance, 30 and we observed herein increased expression of these genes after vorinostat treatment.…”

Significance of survivin expression: Prognostic value and survival in stage III non-small cell lung cancer

“…Survivin is a protein that is cell cycle-regulated with a robust increase in the G2/M phase in cancer cells (12,13). Survivin is known to be overexpressed and related with more aggressive behavior, increased tumor recurrence, chemotherapy resistance and increased survival in various tumors (6,(14)(15)(16)(17)(18)(19)(20)(21). As a prognostic factor, survivin expression is significantly associated with a poor clinical outcome in certain types of cancer, including liver (2), colorectal and breast (3,6).…”

Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

“…[13][14][15] Patient ALL samples and cell lines Primary pre-B ALL samples were used for in vivo and in vitro as described in "Supplemental Methods." 12 …”

“…12 Quantitative reverse transcriptase-polymerase chain reaction (PCR), PCR, and flow cytometry Information is listed in "Supplemental Methods" and supplemental Tables 1 and 2. [13][14][15] Patient ALL samples and cell lines Primary pre-B ALL samples were used for in vivo and in vitro as described in "Supplemental Methods."…”