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Acute Leukemias

Endogenous knockdown of survivin improves chemotherapeutic response in ALL models

Leukemia volume 26, pages 271–279 (2012)Cite this article

Abstract

Although the cure rate of newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past four decades, the outcome for patients who relapse remains poor. New therapies are needed for these patients. Our previous global gene expression analysis in a series of paired diagnosis-relapse pediatric patient samples revealed that the antiapoptotic gene survivin was consistently upregulated upon disease relapse. In this study, we demonstrate a link between survivin expression and drug resistance and test the efficacy of a novel antisense agent in promoting apoptosis when combined with chemotherapy. Gene-silencing experiments targeting survivin mRNA using either short-hairpin RNA (shRNA) or a locked antisense oligonucleotide (LNA-ON) specifically reduced gene expression and induced apoptosis in leukemia cell lines. When used in combination with chemotherapy, the survivin shRNA and LNA-ON potentiated the chemotherapeutic antileukemia effect. Moreover, in a mouse primary xenograft model of relapse ALL, the survivin LNA-ON decreased survivin expression in a subset of animals, and produced a statistically significant decrease in tumor progression. Taken together, these findings suggest that targeting endogenous levels of survivin mRNA by LNA-ON methods may augment the response to standard chemotherapy by sensitizing otherwise resistant tumor cells to chemotherapy.

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References

  1. Bhojwani D, Kang H, Moskowitz NP, Min DJ, Lee H, Potter JW et al. Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 2006; 108: 711–717.

    Article  CAS  Google Scholar 

  2. Knauer SK, Bier C, Schlag P, Fritzmann J, Dietmaier W, Rodel F et al. The survivin isoform survivin-3B is cytoprotective and can function as a chromosomal passenger complex protein. Cell Cycle 2007; 6: 1502–1509.

    CAS  Google Scholar 

  3. Pennati M, Folini M, Zaffaroni N . Targeting survivin in cancer therapy: fulfilled promises and open questions. Carcinogenesis 2007; 28: 1133–1139.

    Article  CAS  Google Scholar 

  4. Fukuda S, Pelus LM . Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 2006; 5: 1087–1098.

    Article  CAS  Google Scholar 

  5. Engels K, Knauer SK, Metzler D, Simf C, Struschka O, Bier C et al. Dynamic intracellular survivin in oral squamous cell carcinoma: underlying molecular mechanism and potential as an early prognostic marker. J Pathol 2007; 211: 532–540.

    Article  CAS  Google Scholar 

  6. Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC et al. Regulation of survivin function by Hsp90. Proc Natl Acad Sci USA 2003; 100: 13791–13796.

    Article  CAS  Google Scholar 

  7. Hattori M, Sakamoto H, Satoh K, Yamamoto T . DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c-erbB-2 and survivin genes. Cancer Lett 2001; 169: 155–164.

    Article  CAS  Google Scholar 

  8. Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E et al. High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000; 19: 617–623.

    Article  CAS  Google Scholar 

  9. Capalbo G, Rodel C, Stauber RH, Knauer SK, Bache M, Kappler M et al. The role of survivin for radiation therapy. Prognostic and predictive factor and therapeutic target. Strahlenther Onkol 2007; 183: 593–599.

    Article  Google Scholar 

  10. Saito T, Arifin MT, Hama S, Kajiwara Y, Sugiyama K, Yamasaki F et al. Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker. J Neurooncol 2007; 82: 193–198.

    Article  CAS  Google Scholar 

  11. Vaira V, Lee CW, Goel HL, Bosari S, Languino LR, Altieri DC . Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 2007; 26: 2678–2684.

    Article  CAS  Google Scholar 

  12. Ling X, Bernacki RJ, Brattain MG, Li F . Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest. J Biol Chem 2004; 279: 15196–15203.

    Article  CAS  Google Scholar 

  13. Tirro E, Consoli ML, Massimino M, Manzella L, Frasca F, Sciacca L et al. Altered expression of c-IAP1, survivin, and Smac contributes to chemotherapy resistance in thyroid cancer cells. Cancer Res 2006; 66: 4263–4272.

    Article  CAS  Google Scholar 

  14. Zhou M, Gu L, Li F, Zhu Y, Woods WG, Findley HW . DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther 2002; 303: 124–131.

    Article  CAS  Google Scholar 

  15. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J et al. Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 2000; 96: 1921–1925.

    CAS  Google Scholar 

  16. Als AB, Dyrskjot L, von der Maase H, Koed K, Mansilla F, Toldbod HE et al. Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res 2007; 13 (15 Part 1): 4407–4414.

    Article  CAS  Google Scholar 

  17. Fangusaro JR, Caldas H, Jiang Y, Altura RA . Survivin: an inhibitor of apoptosis in pediatric cancer. Pediatr Blood Cancer 2006; 47: 4–13.

    Article  Google Scholar 

  18. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351: 2817–2826.

    Article  CAS  Google Scholar 

  19. Smith SD, Wheeler MA, Plescia J, Colberg JW, Weiss RM, Altieri DC . Urine detection of survivin and diagnosis of bladder cancer. JAMA 2001; 285: 324–328.

    Article  CAS  Google Scholar 

  20. Watanuki-Miyauchi R, Kojima Y, Tsurumi H, Hara T, Goto N, Kasahara S et al. Expression of survivin and of antigen detected by a novel monoclonal antibody, T332, is associated with outcome of diffuse large B-cell lymphoma and its subtypes. Pathol Int 2005; 55: 324–330.

    Article  CAS  Google Scholar 

  21. Carter BZ, Andreeff M . Targeting survivin in leukemia. Oncol Rev 2008; 1: 195–204.

    Article  Google Scholar 

  22. Hansen JB, Fisker N, Westergaard M, Kjaerulff LS, Hansen HF, Thrue CA et al. SPC3042: a proapoptotic survivin inhibitor. Mol Cancer Ther 2008; 7: 2736–2745.

    Article  CAS  Google Scholar 

  23. Stein CA, Hansen JB, Lai J, Wu S, Voskresenskiy A, Hog A et al. Efficient gene silencing by delivery of locked nucleic acid antisense oligonucleotides, unassisted by transfection reagents. Nucleic Acids Res 2010; 38: e3.

    Article  CAS  Google Scholar 

  24. Min DJ, Moskowitz NP, Brownstein C, Lee H, Horton TM, Carroll WL . Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines. Apoptosis 2006; 11: 1977–1986.

    Article  CAS  Google Scholar 

  25. Teachey DT, Sheen C, Hall J, Ryan T, Brown VI, Fish J et al. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood 2008; 112: 2020–2023.

    Article  CAS  Google Scholar 

  26. Carter BZ, Mak DH, Schober WD, McQueen T, Harris D, Estrov Z et al. Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells. Blood 2006; 108: 630–637.

    Article  CAS  Google Scholar 

  27. Hogan L, Bhojwani D, Wang J, Morrison D, Yang J, Zhang Y et al. Upregulation of genes involved in folate metabolism characterize late but not early relapse in childhood acute lymphoblastic leukemia. Blood [abstract] 2009; 114: 689.

    Google Scholar 

  28. Sapra P, Wang M, Bandaru R, Zhao H, Greenberger LM, Horak ID . Down-modulation of survivin expression and inhibition of tumor growth in vivo by EZN-3042, a locked nucleic acid antisense oligonucleotide. Nucleosides Nucleotides Nucl Acids 2010; 29: 97–112.

    Article  CAS  Google Scholar 

  29. Hu H, Shikama Y, Matsuoka I, Kimura J . Terminally differentiated neutrophils predominantly express Survivin-2 alpha, a dominant-negative isoform of survivin. J Leukoc Biol 2008; 83: 393–400.

    Article  CAS  Google Scholar 

  30. Altieri DC . Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 2008; 8: 61–70.

    Article  CAS  Google Scholar 

  31. Lee CW, Simin K, Liu Q, Plescia J, Guha M, Khan A et al. A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 2008; 10: R97.

    Article  Google Scholar 

  32. Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T et al. Interplay among BRCA1, SIRT1, and survivin during BRCA1-associated tumorigenesis. Mol Cell 2008; 32: 11–20.

    Article  Google Scholar 

  33. Hayashi N, Asano K, Suzuki H, Yamamoto T, Tanigawa N, Egawa S et al. Adenoviral infection of survivin antisense sensitizes prostate cancer cells to etoposide in vivo. Prostate 2005; 65: 10–19.

    Article  CAS  Google Scholar 

  34. Li QX, Zhao J, Liu JY, Jia LT, Huang HY, Xu YM et al. Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers. Cancer Biol Ther 2006; 5: 860–866.

    Article  CAS  Google Scholar 

  35. Nakao K, Hamasaki K, Ichikawa T, Arima K, Eguchi K, Ishii N . Survivin downregulation by siRNA sensitizes human hepatoma cells to TRAIL-induced apoptosis. Oncol Rep 2006; 16: 389–392.

    Article  CAS  Google Scholar 

  36. Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Res 2000; 60: 2805–2809.

    CAS  Google Scholar 

  37. Yonesaka K, Tamura K, Kurata T, Satoh T, Ikeda M, Fukuoka M et al. Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin. Int J Cancer 2006; 118: 812–820.

    Article  CAS  Google Scholar 

  38. Kim R, Emi M, Matsuura K, Tanabe K . Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy. Cancer Gene Ther 2007; 14: 1–11.

    Article  CAS  Google Scholar 

  39. Fangusaro JR, Jiang Y, Holloway MP, Caldas H, Singh V, Boue DR et al. Survivin, survivin-2B, and survivin-deItaEx3 expression in medulloblastoma: biologic markers of tumour morphology and clinical outcome. Br J Cancer 2005; 92: 359–365.

    Article  CAS  Google Scholar 

  40. Takamizawa S, Scott D, Wen J, Grundy P, Bishop W, Kimura K et al. The survivin: fas ratio in pediatric renal tumors. J Pediatr Surg 2001; 36: 37–42.

    Article  CAS  Google Scholar 

  41. Tamm I, Richter S, Oltersdorf D, Creutzig U, Harbott J, Scholz F et al. High expression levels of x-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia. Clin Cancer Res 2004; 10: 3737–3744.

    Article  CAS  Google Scholar 

  42. Zhu N, Gu L, Li F, Zhou M . Inhibition of the Akt/survivin pathway synergizes the antileukemia effect of nutlin-3 in acute lymphoblastic leukemia cells. Mol Cancer Ther 2008; 7: 1101–1109.

    Article  CAS  Google Scholar 

  43. Talbot D, Davies J, Callies S, Andre V, Lahn M, Ang J et al. First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin. J Clin Oncol 2008; 26: 3518.

    Article  Google Scholar 

  44. Tolcher AW, Patnaik A, Papadopoulos KP, Agnew J, Lokiec FM, Rezai K et al. Results of a phase 1, open-label, dose-escalation study evaluating the safety and tolerability of EZN-3042, a survivin mRNA antagonist, administered with or without docetaxel in adult patients with advanced solid tumors or lymphoma. Proceedings of the 102nd Annual Meeting of AACR, 2011 LB-409 (abstract).

  45. Tolcher AW, Mita A, Lewis LD, Garrett CR, Till E, Daud AI et al. Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J Clin Oncol 2008; 26: 5198–5203.

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by the National Institute of Health (NIH; 5 RO1 CA 140729-02, 5 P30 CA 01608730), the Pediatric Cancer Foundation, the Penelope London Foundation, Silber Pediatric Leukemia Fund and the Walter Family Pediatric Leukemia Fund. LH is supported by the American Society of Hematology Research Training Award for Fellows and a St Baldrick's Foundation Fellowship. DTT is supported by a Larry and Helen Hoag Foundation Clinical Translational Research Career Development Award and the Leukemia and Lymphoma Society. Enzon Pharmaceuticals provided EZN-3042 and EZN-3046.

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Authors and Affiliations

  1. New York University Cancer Institute and Division of Pediatric Hematology/Oncology, New York University School of Medicine, New York, NY, USA

    D J Morrison, L E Hogan, G Condos, T Bhatla, N Germino, N P Moskowitz, L Lee, E A Raetz & W L Carroll

  2. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA

    D Bhojwani

  3. Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA

    T M Horton

  4. Department of Biostatistics, New York University School of Medicine, New York, NY, USA

    I Belitskaya-Levy

  5. Enzon Pharmaceuticals, Inc., Piscataway, NJ, USA

    L M Greenberger & I D Horak

  6. Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA,

    S A Grupp & D T Teachey

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Correspondence to W L Carroll.

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LMG and IDH are employees of Enzon Pharmaceuticals. The remaining authors declare no conflict of interest.

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Morrison, D., Hogan, L., Condos, G. et al. Endogenous knockdown of survivin improves chemotherapeutic response in ALL models. Leukemia 26, 271–279 (2012). https://doi.org/10.1038/leu.2011.199

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