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Expression of activation-induced cytidine deaminase is associated with a poor prognosis of diffuse large B cell lymphoma patients treated with CHOP-based chemotherapy

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Activation-induced cytidine deaminase (AID) is involved in somatic hypermutation and class switch recombination processes in the antibody formation. The AID activity induces gene mutations and could be associated with transformation processes of B cells. Nevertheless, the relation between AID expression and the prognosis of B cell lymphoma patients remains uncharacterized.

Methods

We examined expression levels of the AID gene in 89 lymph node specimens from lymphoma and non-lymphoma patients with Northern blot analysis and investigated an association with their survival.

Results

The AID gene was preferentially expressed in B cell lymphoma in particular in diffuse large B cell lymphoma and follicular lymphoma. We confirmed AID protein expression in the mRNA-positive but not in the negative specimens with Western blot analysis and immunohistochemical staining. Survival of the patients treated with cyclophosphamide-/doxorubicin-/vincristine-/prednisone-based chemotherapy demonstrated that the prognosis of diffuse large B cell patients was unfavorable in the mRNA-positive group compared with the negative group, and that AID expression levels were correlated with the poor prognosis. In contrast, AID expression was not linked with the prognosis of follicular lymphoma patients.

Conclusions

AID expression is a predictive marker for an unfavorable outcome in DLBCL patients treated with the chemotherapy.

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References

  • Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR et al (2003) Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 102:3333–3339

    Article  PubMed  CAS  Google Scholar 

  • Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S et al (2005) The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438:508–511

    Article  PubMed  CAS  Google Scholar 

  • Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

    Article  PubMed  CAS  Google Scholar 

  • Degan M, Bomben R, Bo MD, Zucchetto A, Nanni P et al (2004) Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery. Br J Haematol 126:29–42

    Article  PubMed  CAS  Google Scholar 

  • Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K et al (2003) Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. Blood 101:3574–3580

    Article  PubMed  CAS  Google Scholar 

  • Hardianti MS, Tatsumi E, Syampurnawati M, Furuta K, Saigo K et al (2004) Activation-induced cytidine deaminase expression in follicular lymphoma: association between AID expression and ongoing mutation in FL. Leukemia 18:826–831

    Article  PubMed  CAS  Google Scholar 

  • Heintel D, Kroemer E, Kienle D, Schwarzinger I, Gleiss A et al (2004) High expression of activation-induced cytidine deaminase (AID) mRNA is associated with unmutated IGVH gene status and unfavourable cytogenetic aberrations in patients with chronic lymphocytic leukaemia. Leukemia 18:756–762

    Article  PubMed  CAS  Google Scholar 

  • Kinoshita K, Honjo T (2001) Linking class-switch recombination with somatic hypermutation. Nat Rev Mol Cell Biol 2:493–503

    Article  PubMed  CAS  Google Scholar 

  • Leuenberger M, Frigerio S, Wild PJ, Noetzli F, Korol D et al (2010) AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations. Mod Pathol 23:177–186

    Article  PubMed  CAS  Google Scholar 

  • Liu JQ, Joshi PS, Wang C, El-Omrani HY, Xiao Y et al (2010) Targeting activation-induced cytidine deaminase overcomes tumor evasion of immunotherapy by CTLs. J Immunol 184:5435–5443

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lossos IS, Levy R, Alizadeh AA (2004) AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity. Leukemia 18:1775–1779

    Article  PubMed  CAS  Google Scholar 

  • Lymphoma Study Group of Japanese Pathologists (2000) The world health organization classification of malignant lymphomas in Japan: incidence of recently recognized entities. Pathol Int 50:696–702

    Article  Google Scholar 

  • Machida K, Cheng KT, Sung VM, Shimodaira S, Lindsay KL et al (2004) Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci USA 101:4262–4267

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T et al (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13:470–476

    Article  PubMed  CAS  Google Scholar 

  • Mechtcheriakova D, Svoboda M, Meshcheryakova A, Jensen-Jarolim E (2012) Activation-induced cytidine deaminase (AID) linking immunity, chronic inflammation, and cancer. Cancer Immunol Immunother 61:1591–1598

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 279:52353–52360

    Article  PubMed  CAS  Google Scholar 

  • Morisawa T, Marusawa H, Ueda Y, Iwai A, Okazaki IM et al (2008) Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. Int J Cancer 123:2735–2740

    Article  PubMed  CAS  Google Scholar 

  • Okazaki IM, Kotani A, Honjo T (2007) Role of AID in tumorigenesis. Adv Immunol 94:245–273

    Article  PubMed  CAS  Google Scholar 

  • Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C et al (2003) Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation. Blood 101:4029–4032

    Article  PubMed  CAS  Google Scholar 

  • O-Wang J, Kawamura K, Tada Y, Ohmori H, Kimura H et al (2001) DNA polymerase kappa, implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer. Cancer Res 61:5366–5369

    PubMed  CAS  Google Scholar 

  • Palacios F, Moreno P, Morande P, Abreu C, Correa A et al (2010) High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease. Blood 115:4488–4496

    Article  PubMed  CAS  Google Scholar 

  • Pasqualucci L, Guglielmino R, Houldsworth J, Mohr J, Aoufouchi S et al (2004) Expression of the AID protein in normal and neoplastic B cells. Blood 104:3318–3325

    Article  PubMed  CAS  Google Scholar 

  • Petersen-Mahrt SK, Harris RS, Neuberger MS (2002) AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418:99–103

    Article  PubMed  CAS  Google Scholar 

  • Revy P, Muto T, Levy Y, Geissmann F, Plebani A et al (2000) Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102:565–575

    Article  PubMed  CAS  Google Scholar 

  • Smith LA, Bende RJ, Aten J, Guikema JE, Aarts WM et al (2003) Expression of activation-induced cytidine deaminase is confined to B-cell non-Hodgkin’s lymphomas of germinal-center phenotype. Cancer Res 63:3894–3898

    Google Scholar 

  • Ta VT, Nagaoka H, Catalan N, Durandy A, Fischer A et al (2003) AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat Immunol 4:843–848

    Article  PubMed  CAS  Google Scholar 

  • Wang CL, Harper RA, Wabl M (2004) Genome-wide somatic hypermutation. Proc Natl Acad Sci USA 101:7352–7356

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Willenbrock K, Renné C, Rottenkolber M, Klapper W, Dreyling M et al (2009) The expression of activation induced cytidine deaminase in follicular lymphoma is independent of prognosis and stage. Histopathology 54:509–512

    Article  PubMed  Google Scholar 

  • Wu X, Geraldes P, Platt JL, Cascalho M (2005) The double-edged sword of activation-induced cytidine deaminase. J Immunol 174:934–941

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa K, Okazaki IM, Eto T, Kinoshita K, Muramatsu M et al (2002) AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296:2033–2036

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Ms Kimiko Takayama, Division of Epidemiology, Chiba Cancer Center Research Institute for confirmation of patients’ survival data. The study is supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Grant-in-Aid for Research on Seeds for Publicly Essential Drugs and Medical Devices from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-aid from the Nichias Corporation.

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan

    Kiyoko Kawamura, Akihiko Wada, Quanhai Li & Masatoshi Tagawa

  2. Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Akihiko Wada, Yuji Tada & Koichiro Tatsumi

  3. Department of Immunology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, China

    Ji-Yang Wang

  4. Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Ji-Yang Wang

  5. Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Quanhai Li & Masatoshi Tagawa

  6. Division of Hematology-Oncology, Chiba Cancer Center, 66-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan

    Akihiro Ishii, Hideki Tsujimura & Toshiyuki Takagi

  7. Division of Surgical Pathology, Chiba Cancer Center, 66-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan

    Makiko Itami

  8. Department of Surgery, School of Medicine, Toho University, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan

    Hideaki Shimada

  9. Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owadasinden, Yachiyo, 276-8524, Japan

    Kenzo Hiroshima

Authors
  1. Kiyoko Kawamura
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  2. Akihiko Wada
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  3. Ji-Yang Wang
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  4. Quanhai Li
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  5. Akihiro Ishii
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  6. Hideki Tsujimura
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  7. Toshiyuki Takagi
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  8. Makiko Itami
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  9. Yuji Tada
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  10. Koichiro Tatsumi
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  11. Hideaki Shimada
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  12. Kenzo Hiroshima
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  13. Masatoshi Tagawa
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Corresponding author

Correspondence to Masatoshi Tagawa.

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Kawamura, K., Wada, A., Wang, JY. et al. Expression of activation-induced cytidine deaminase is associated with a poor prognosis of diffuse large B cell lymphoma patients treated with CHOP-based chemotherapy. J Cancer Res Clin Oncol 142, 27–36 (2016). https://doi.org/10.1007/s00432-015-2001-7

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  • DOI: https://doi.org/10.1007/s00432-015-2001-7

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