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Lymphoma

Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

Leukemia volume 21, pages 772–779 (2007)Cite this article

Abstract

The status of the p53 pathway in classical Hodgkin lymphoma (cHL) remains unclear, and a lack of proven TP53 mutations contrasts with often high expression levels of p53 protein. In this study, we demonstrate that pharmacologic activation of the p53 pathway with the murine double minute 2 (MDM2) antagonist nutlin-3 in Hodgkin lymphoma-derived cell lines leads to effective apoptosis induction and sensitizes the cells to other anticancer drugs. Cells with mutant p53 are resistant to nutlin-3, but sensitive to geldanamycin, a pharmacologic inhibitor of heat shock 90 kDa protein (HSP90), indicating that HSP90 inhibition can induce apoptosis in a p53-independent manner. Conversely, cells with defects in the HSP90/nuclear factor-κ B pathway expressing wild-type p53 are more resistant to geldanamycin, but still sensitive to nutlin-3. Our results suggest that selective activation of p53 by MDM2 antagonists as a single agent or in combination with conventional chemotherapeutics and/or inhibitors of p53-independent survival pathways may offer effective treatment options for patients with cHL. Importantly, because nutlins and HSP90 inhibitors are non-genotoxic agents, their use might offer a means to reduce the genotoxic burden of current chemotherapeutic regimens.

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References

  1. Stein H, Delsol G, Pileri S, Said J, Mann R, Poppema S et al. Classical Hodgkin Lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, (eds). World Health Organization classification of tumorsPathology and genetics of tumors of haematopoietic and lymphoid tissues. IARC Press, Lyon, 2001, 244–253.

    Google Scholar 

  2. Josting A, Wiedenmann S, Franklin J, May M, Sieber M, Wolf J et al. Secondary myeloid leukemia and myelodysplastic syndromes in patients treated for Hodgkin's disease: a report from the German Hodgkin's Lymphoma Study Group. J Clin Oncol 2003; 21: 3440–3446.

    Article  Google Scholar 

  3. Lin H-MJ, Teitell MA . Second malignancy after treatment of pediatric Hodgkin disease. J Pediatr Hematol Oncol 2005; 27: 28–36.

    Article  Google Scholar 

  4. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–848.

    Article  CAS  Google Scholar 

  5. Stühmer T, Chatterjee M, Hildebrandt M, Herrmann P, Gollasch H, Gerecke C et al. Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 2005; 106: 3609–3617.

    Article  Google Scholar 

  6. Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood 2005; 106: 3150–3159.

    Article  CAS  Google Scholar 

  7. Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci USA 2006; 103: 1888–1893.

    Article  CAS  Google Scholar 

  8. Bond GL, Hu W, Levine AJ . MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 2005; 5: 3–8.

    Article  CAS  Google Scholar 

  9. Peller S, Rotter V . TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum Mutat 2003; 21: 277–284.

    Article  CAS  Google Scholar 

  10. Küpper M, Joos S, von Bonin F, Daus H, Pfreundschuh M, Lichter P et al. MDM2 gene amplification and lack of p53 point mutations in Hodgkin and Reed-Sternberg cells: results from single-cell polymerase chain reaction and molecular cytogenetic studies. Br J Haematol 2001; 112: 768–775.

    Article  Google Scholar 

  11. Maggio EM, Stekelenburg E, Van Den Berg A, Poppema S . TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein–Barr virus. Int J Cancer 2001; 94: 60–66.

    Article  CAS  Google Scholar 

  12. Montesinos-Rongen M, Roers A, Küppers R, Rajewsky K, Hansmann M-L . Mutation of the p53 gene is not a typical feature of Hodgkin and Reed–Sternberg cells in Hodgkin's disease. Blood 1999; 94: 1755–1760.

    CAS  Google Scholar 

  13. Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W et al. Constitutive nuclear factor-κB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 1997; 100: 2961–2969.

    Article  CAS  Google Scholar 

  14. Emmerich F, Meiser M, Hummel M, Demel G, Foss H-D, Jundt F et al. Overexpression of I kappa B alpha without inhibition of NF-κB activity and mutations in the I kappa B alpha gene in Reed–Sternberg cells. Blood 1999; 94: 3129–3134.

    CAS  Google Scholar 

  15. Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Döhner K et al. Inactivating I kappa B epsilon mutations in Hodgkin/Reed–Sternberg cells. J Pathol 2003; 201: 413–420.

    Article  CAS  Google Scholar 

  16. Broemer M, Krappmann D, Scheidereit C . Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation. Oncogene 2004; 23: 5378–5386.

    Article  CAS  Google Scholar 

  17. Whitesell L, Lindquist SL . HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005; 5: 761–772.

    Article  CAS  Google Scholar 

  18. Chatterjee M, Stühmer T, Herrmann P, Bommert K, Dörken B, Bargou RC . Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells. Blood 2004; 104: 3712–3721.

    Article  CAS  Google Scholar 

  19. Brummelkamp TR, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550–553.

    Article  CAS  Google Scholar 

  20. Harvey RJ, Vreugdenhil E, Zaman SH, Bhandal NS, Usherwood PNR, Barnard EA et al. Sequence of a functional invertebrate GABAA receptor subunit which can form a chimeric receptor with a vertebrate α subunit. EMBO J 1991; 10: 3239–3245.

    Article  CAS  Google Scholar 

  21. Elenitoba-Johnson KS, Medeiros LJ, Khorsand J, King TC . P53 expression in Reed–Sternberg cells does not correlate with gene mutations in Hodgkin's disease. Am J Clin Pathol 1996; 106: 728–738.

    Article  CAS  Google Scholar 

  22. Garcia JF, Villuendas R, Sánchez-Beato M, Sánchez-Aguilera A, Sánchez L, Prieto I et al. Nucleolar p14ARF overexpression in Reed–Sternberg cells in Hodgkin's lymphoma. Am J Pathol 2002; 160: 569–578.

    Article  CAS  Google Scholar 

  23. Mathas S, Lietz A, Janz M, Hinz M, Jundt F, Scheidereit C et al. Inhibition of NF-κB essentially contributes to arsenic-induced apoptosis. Blood 2003; 102: 1028–1034.

    Article  CAS  Google Scholar 

  24. Blagosklonny MV . p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect. FASEB J 2000; 14: 1901–1907.

    Article  CAS  Google Scholar 

  25. Georgakis GV, Li Y, Rassidakis GZ, Martinez-Valdez H, Medeiros LJ, Younes A . Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's Lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death. Clin Cancer Res 2006; 12: 584–590.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe KFO 105) and the Deutsche Krebshilfe (10-2225-Ja 1). We thank Pia Herrmann, Brigitte Wollert-Wulf, Margarete Gries and Evelyn Grella for excellent technical assistance, Andreas Lietz for advice on NF-κB p65 overexpression experiments and Stephan Mathas for critical reading of this paper.

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Author notes

  1. M Janz and T Stühmer: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Hematology, Oncology and Tumorimmunology, Max Delbrück Center for Molecular Medicine, Berlin, Germany

    M Janz

  2. Department of Hematology, Oncology and Tumorimmunology, Charité, Universitätsmedizin Berlin, Campus Buch and Campus Virchow-Klinikum, Berlin, Germany

    M Janz

  3. Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany

    T Stühmer & R C Bargou

  4. Discovery Oncology, Hoffmann-La Roche Inc., Nutley, NJ, USA

    L T Vassilev

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  1. M Janz
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  2. T Stühmer
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  3. L T Vassilev
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  4. R C Bargou
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Corresponding author

Correspondence to T Stühmer.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Janz, M., Stühmer, T., Vassilev, L. et al. Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells. Leukemia 21, 772–779 (2007). https://doi.org/10.1038/sj.leu.2404565

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