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Prognostic significance of PRAME expression based on immunohistochemistry for diffuse large B-cell lymphoma patients treated with R-CHOP therapy

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Abstract

The preferentially expressed antigen of melanoma (PRAME), a tumor-associated antigen, is considered a prognostic marker for various human malignancies. The prognostic significance of PRAME expression for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-containing chemotherapy has not been evaluated to date, and the ability of immunohistochemistry (IHC) to detect PRAME expression in these patients has not yet been studied, although IHC is simple to perform in clinical practice. We evaluated the prognostic significance of PRAME expression based on IHC analysis in 160 DLBCL patients treated with R-CHOP therapy. There was a significant association between higher PRAME expression and shorter progression-free survival (PFS), and a trend toward shorter overall survival (OS) in patients with higher PRAME expression than that in patients with lower PRAME expression (5-year PFS, 48.1 vs. 61.1 %; 5-year OS, 65.6 vs. 79.1 %). Patients with high PRAME expression tended to have lower chemotherapeutic responses. Thus, IHC is useful for detecting and assessing PRAME expression in DLBCL. Further, we found a positive correlation between IHC and quantitative real-time RT-PCR measurements of PRAME expression. Our findings indicate that IHC results of PRAME expression can be a novel prognostic maker in DLBCL patients treated with R-CHOP therapy.

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References

  1. Ikeda H, Lethé B, Lehmann F, Van Baren N, Baurain JF, de Smet C, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6:199–208.

    Article  CAS  PubMed  Google Scholar 

  2. van Baren N, Chambost H, Ferrant A, Michaux L, Ikeda H, Millard I, et al. PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukaemia cells. Br J Haematol. 1998;102:1376–9.

    Article  PubMed  Google Scholar 

  3. Epping MT, Hart AA, Glas AM, Krijgsman O, Bernards R. PRAME expression and clinical outcome of breast cancer. Br J Cancer. 2008;99:398–403.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Tan P, Zou C, Yong B, Han J, Zhang L, Su Q, et al. Expression and prognostic relevance of PRAME in primary osteosarcoma. Biochem Biophys Res Commun. 2012;419:801–8.

    Article  CAS  PubMed  Google Scholar 

  5. Oberthuer A, Hero B, Spitz R, Berthold F, Fischer M. The tumor-associated antigen PRAME is universally expressed in high-stage neuroblastoma and associated with poor outcome. Clin Cancer Res. 2004;10:4307–13.

    Article  CAS  PubMed  Google Scholar 

  6. Proto-Siqueira R, Falcão RP, de Souza CA, Ismael SJ, Zago MA. The expression of PRAME in chronic lymphoproliferative disorders. Leuk Res. 2003;27:393–6.

    Article  CAS  PubMed  Google Scholar 

  7. Paydas S, Tanriverdi K, Yavuz S, Seydaoglu G. PRAME mRNA levels in cases with chronic leukemia: clinical importance and review of the literature. Leuk Res. 2007;31:365–9.

    Article  CAS  PubMed  Google Scholar 

  8. Paydas S, Tanriverdi K, Yavuz S, Disel U, Baslamisli F, Burgut R. PRAME mRNA levels in cases with acute leukemia: clinical importance and future prospects. Am J Hematol. 2005;79:257–61.

    Article  CAS  PubMed  Google Scholar 

  9. Tanaka N, Wang YH, Shiseki M, Takanashi M, Motoji T. Inhibition of PRAME expression causes cell cycle arrest and apoptosis in leukemic cells. Leuk Res. 2011;35:1219–25.

    Article  CAS  PubMed  Google Scholar 

  10. Watari K, Tojo A, Nagamura-Inoue T, Nagamura F, Takeshita A, Fukushima T, et al. Identification of a melanoma antigen, PRAME, as a BCR/ABL-inducible gene. FEBS Lett. 2000;466:367–71.

    Article  CAS  PubMed  Google Scholar 

  11. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci. 2006;103:2794–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Steinbach D, Hermann J, Viehmann S, Zintl F, Gruhn B. Clinical implications of PRAME gene expression in childhood acute myeloid leukemia. Cancer Genet Cytogenet. 2002;133:118–23.

    Article  CAS  PubMed  Google Scholar 

  13. Steinbach D, Viehmann S, Zintl F, Gruhn B. PRAME gene expression in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet. 2002;138:89–91.

    Article  CAS  PubMed  Google Scholar 

  14. Epping MT, Wang L, Edel MJ, Carlée L, Hernandez M, Bernards R. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122:835–47.

    Article  CAS  PubMed  Google Scholar 

  15. Kewitz S, Staege MS. Knock-down of PRAME increases retinoic acid signaling and cytotoxic drug sensitivity of Hodgkin lymphoma cells. PLoS One. 2013;8:e55897.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Lossos IS. Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Oncol. 2005;23:6351–7.

    Article  CAS  PubMed  Google Scholar 

  17. Hermine O, Haioun C, Lepage E, d’Agay MF, Briere J, Lavignac C, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 1996;87:265–72.

    CAS  PubMed  Google Scholar 

  18. Lossos IS, Jones CD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL, et al. Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood. 2001;98:945–51.

    Article  CAS  PubMed  Google Scholar 

  19. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.

    Article  CAS  PubMed  Google Scholar 

  20. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera international trial (MInT) Group. Lancet Oncol. 2006;7:379–91.

    Article  CAS  PubMed  Google Scholar 

  21. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116:2040–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, Sebban C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003;101:4279–84.

    Article  CAS  PubMed  Google Scholar 

  23. Winter JN, Weller EA, Horning SJ, Krajewska M, Variakojis D, Habermann TM, et al. Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correlative study. Blood. 2006;107:4207–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Nyman H, Adde M, Karjalainen-Lindsberg ML, Taskinen M, Berglund M, Amini RM, et al. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood. 2007;109:4930–5.

    Article  CAS  PubMed  Google Scholar 

  25. Kawano R, Karube K, Kikuchi M, Takeshita M, Tamura K, Uike N, et al. Oncogene associated cDNA microarray analysis shows PRAME gene expression is a marker for response to anthracycline containing chemotherapy in patients with diffuse large B-cell lymphoma. J Clin Exp Hematop. 2009;49:1–7.

    Article  PubMed  Google Scholar 

  26. Moormeier JA, Williams SF, Golomb HM. The staging of non-Hodgkin’s lymphomas. Semin Oncol. 1990;17:43–50.

    CAS  PubMed  Google Scholar 

  27. A predictive model for aggressive non-Hodgkin’s lymphoma. the International non-Hodgkin’s lymphoma prognostic factors project. N Engl J Med. 1993;329:987–94.

  28. Salles G, de Jong D, Xie W, Rosenwald A, Chhanabhai M, Gaulard P, et al. Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg lymphoma biomarker consortium. Blood. 2011;117:7070–8.

    Article  PubMed  Google Scholar 

  29. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.

    Article  CAS  PubMed  Google Scholar 

  30. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460–7.

    Article  CAS  PubMed  Google Scholar 

  31. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.

    Article  PubMed  Google Scholar 

  32. Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A, et al. Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches. Blood. 2006;108:4109–17.

    Article  CAS  PubMed  Google Scholar 

  33. Bullinger L, Schlenk RF, Götz M, Botzenhardt U, Hofmann S, Russ AC, et al. PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation–a possible target for ATRA response in AML without t(15;17). Clin Cancer Res. 2013;19:2562–71.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank all the physicians who were involved in the expert care of the patients during the study period. We also thank the laboratory technicians of the Department of Hematology and Surgical Pathology for excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Hematology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Kenjiro Mitsuhashi, Yan-Hua Wang, Masayuki Shiseki & Toshiko Motoji

  2. Department of Surgical Pathology, Tokyo Women’s Medical University, Tokyo, Japan

    Akihiro Masuda

Authors
  1. Kenjiro Mitsuhashi
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  2. Akihiro Masuda
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  3. Yan-Hua Wang
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  4. Masayuki Shiseki
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  5. Toshiko Motoji
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Correspondence to Kenjiro Mitsuhashi.

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Mitsuhashi, K., Masuda, A., Wang, YH. et al. Prognostic significance of PRAME expression based on immunohistochemistry for diffuse large B-cell lymphoma patients treated with R-CHOP therapy. Int J Hematol 100, 88–95 (2014). https://doi.org/10.1007/s12185-014-1593-z

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  • DOI: https://doi.org/10.1007/s12185-014-1593-z

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