Abstract
Activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin (Ig) gene. AID has been reported to be specifically expressed in the germinal center (GC). Follicular lymphoma (FL) cells are known to be exposed to GC reaction, as characterized by a high degree of SHM with some heterogeneity in terms of intraclonal microheterogeneity and antigen selection. The heterogeneity of SHM pattern in FL intrigued us to investigate the AID expression. AID expression was investigated in 19 FL materials consisting of 15 cases of FL fresh cells and four cell lines. In all, 10 fresh cells and three cell lines expressed AID, but the others did not. SHM was investigated in 12 fresh cells and four cell lines. The ongoing mutation was significantly different between AID-positive and AID-negative FL fresh cells (unpaired Student's t-test, P=0.047). Ongoing mutation was not seen in any of the cell lines. AID expression was associated with the ongoing mutation in FL fresh cells (two-tailed Pearson's coefficient correlation, r=0.899, P=0.01). The switch off of AID expression may start in the B-lineage differentiation stage counterpart of FL after optimizing SHM, indicated by the cessation of the ongoing mutation in AID-negative FL fresh cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Janeway CA, Travers P, Walport M . The generation of diversity in the humoral immune response. In: Immunobiology: The Immune System in Health and Disease, 4th edn. New York: Garland, 1999, pp 90–101.
Kinoshita K, Honjo T . Linking class–switch recombination with somatic hypermutation. Nat Rev Mol Cell Biol 2001; 2: 493–503.
Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, Davidson NO et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem 1999; 274: 18470–18476.
Kosmas C, Stamatopoulos K, Papadaki T, Belessi C, Yataganas X, Anagnostou D et al. Somatic hypermutation of immunoglobulin variable region genes: focus on follicular lymphoma and multiple myeloma. Immunol Rev 1998; 162: 281–292.
Bahler DW, Zelenetz AD, Chen TT, Levy R . Antigen selection in human lymphomagenesis. Cancer Res 1992; 52 (Suppl): 5547s–5551s.
Dighiero G, Hart S, Lim A, Borche L, Levy R, Miller RA . Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas. Blood 1991; 78: 581–585.
Levy R, Levy S, Cleary ML, Carrol W, Kon S, Bird J et al. Somatic mutation in human B-cell tumors. Immunol Rev 1987; 96: 43–58.
Zhu D, Hawkins RE, Hamblin TJ, Stevenson FK . Clonal history of a human follicular lymphoma as revealed in the immunoglobulin variable region genes. Br J Haematol 1994; 86: 505–512.
Stevenson FK, Spellerberg MB, Treasure J, Chapman CJ, Silberstein LE, Hamblin TJ et al. Differential usage of an Ig heavy chain variable region gene by human B-cell tumors. Blood 1993; 8: 224–230.
Noppe SM, Heirman C, Bakkus MH, Brissinck J, Schots R, Thielemans K . The genetic variability of the VH genes in follicular lymphoma: the impact of the hypermutation mechanism. Br J Haematol 1999; 107: 625–640.
Ohno H, Doi S, Fukuhara S, Nishikori M, Uchino H, Fujii H . A newly established human lymphoma cell line, FL-18, carrying a 14;18 translocation. Jpn J Cancer Res 1985; 76: 563–566.
Amakawa R, Fukuhara S, Ohno H, Tanabe S, Horii M, Matsuyama F et al. Amplified and rearranged bcl-2 gene in two lymphoma cell lines, FL-218 and FL-318, carrying a 14;18 translocation. Cancer Res 1990; 50: 2423–2428.
Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 2000; 102: 565–575.
McCarthy H, Wierda WG, Barron LL, Cromwell CC, Wang J, Coombes KR et al. High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor prognostic chronic lymphocytic leukemia. Blood 2003; 101: 4903–4908.
Ponte P, Ng SY, Engel J, Gunning P, Kedes L . Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res 1984; 12: 1687–1696.
Taniguchi M, Oka K, Hiasa A, Yamaguchi M, Ohno T, Kita K et al. De novo CD5+ diffuse large B-cell lymphomas express VH genes with somatic mutation. Blood 1998; 91: 1145–1151.
Dorner T, Foster SJ, Brezinschek HP, Lipsky PE . Analysis of the targeting of the hypermutational machinery and the impact of subsequent selection on the distribution of nucleotide changes in human VHDJH rearrangements. Immunol Rev 1998; 162: 161–171.
Klein U, Goossens T, Fischer M, Kanzler H, Braeuninger A, Rajewsky K et al. Somatic hypermutation in normal and transformed human B cells. Immunol Rev 1998; 162: 261–280.
Gurrieri C, McGuire P, Zan H, Yan XJ, Cerutti A, Albesiano E et al. Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification. J Exp Med 2002; 196: 629–639.
Sykes PJ In: Faguet GB (ed) Hematologic Malignancies: Methods and Techniques. Totowa, NJ: Humana Press Inc., 2001, pp 117–130.
Bahler DW, Campbell MJ, Hart S, Miller RA, Levy S, Levy R . IgVH gene expression among human follicular lymphomas. Blood 1991; 78: 1561–1568.
Aarts WM, Bende RJ, Steenbergen EJ, Kluin PM, Ooms EC, Pals ST et al. Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load. Blood 2000; 95: 2922–2929.
Wilson PC, de Bouteiller O, Liu YJ, Potter K, Banchereau J, Capra JD et al. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J Exp Med 1998; 187: 59–70.
Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K, Castle BE et al. Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin's lymphomas. Blood 2003; 101: 3574–3580.
Hardianti MS, Tatsumi E, Syampurnawati M, Furuta K, Saigo K, Kawano S et al. Expression of activation-induced cytidine deaminase (AID) in Burkitt lymphoma (BL) cells: rare AID-negative cell lines with the unmutated rearranged VH gene. Leukemia Lymphoma 2004; 45: 155–160.
Nakamura F, Tatsumi E, Tani K, Kumagai S, Kosaka Y, Sano K et al. Coexpression of cell-surface immunoglobulin (sIg), terminal deoxynucleotidyl transferase (TdT) and recombination activating gene 1 (RAG-1): two cases and derived cell lines. Leukemia 1996; 10: 1159–1163.
Smit LA, Bende RJ, Aten J, Guikema JE, Aarts WM, van Noesel CJ . Expression of activation-induced cytidine deaminase is confined to B-cell non-Hodgkin's lymphomas of germinal-center phenotype. Cancer Res 2003; 63: 3894–3898.
Denepoux S, Fournier N, Peronne C, Banchereau J, Lebecque S . T cells can induce somatic mutation in B cell receptor-engaged BL2 Burkitt's lymphoma cells independently of CD40-CD40 ligand interactions. J Immunol 2000; 164: 1306–1313.
Zan H, Cerutti A, Dramitinos P, Schaffer A, Li Z, Casali P . Induction of Ig somatic hypermutation and class switching in a human monoclonal IgM+ IgD+ B cell line in vitro: definition of the requirements and modalities of hypermutation. J Immunol 1999; 162: 3437–3447.
Wu H, Pelkonen E, Knuutila S, Kaartinen M . A human follicular lymphoma B cell line hypermutates its functional immunoglobulin genes in vitro. Eur J Immunol 1995; 25: 3263–3269.
Zhang W, Bardwell PD, Woo CJ, Poltoratsky V, Scharff MD, Martin A . Clonal instability of V region hypermutation in the Ramos Burkitt's lymphoma cell line. Int Immunol 2001; 13: 1175–1184.
Chapman CJ, Mockridge CI, Rowe M, Rickinson AB, Stevenson FK . Analysis of VH genes used by neoplastic B cells in endemic Burkitt's lymphoma shows somatic hypermutation and intraclonal heterogeneity. Blood 1995; 85: 2176–2181.
Tamaru J, Hummel M, Marafioti T, Kalvelage B, Leoncini L, Minacci C et al. Burkitt's lymphomas express VH genes with a moderate number of antigen-selected somatic mutations. Am J Pathol 1995; 147: 1398–1407.
Chapman CJ, Zhou JX, Gregory C, Rickinson AB, Stevenson FK . VH and VL gene analysis in sporadic Burkitt's lymphoma shows somatic hypermutation, intraclonal heterogeneity, and a role for antigen selection. Blood 1996; 88: 3562–3568.
Honjo T . Does AID need another aid? Nat Immunol 2002; 3: 800–801.
Faili A, Aoufouchi S, Gueranger Q, Zober C, Leon A, Bertocci B et al. AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line. Nat Immunol 2002; 3: 815–821.
Papavasiliou FN, Schatz DG . The activation-induced deaminase functions in a postcleavage step of the somatic hypermutation process. J Exp Med 2002; 195: 1193–1198.
Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C, Payelle-Brogard B et al. Chronic lymphocytic leukemia B cells expressing AID display a dissociation between class switch recombination and somatic hypermutation. Blood 2003; 101: 4029–4032.
Ottensmeier CH, Thompsett AR, Zhu D, Wilkins BS, Sweetenham JW, Stevenson FK . Analysis of VH genes in follicular and diffuse lymphoma shows ongoing somatic mutation and multiple isotype transcripts in early disease with changes during disease progression. Blood 1998; 91: 4292–4299.
Acknowledgements
MSH is a Graduate Student of Foreign Scholarship of Japan (MONBUSHO) under the superiority of Professor Masafumi Matsuo.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hardianti, M., Tatsumi, E., Syampurnawati, M. et al. Activation-induced cytidine deaminase expression in follicular lymphoma: association between AID expression and ongoing mutation in FL. Leukemia 18, 826–831 (2004). https://doi.org/10.1038/sj.leu.2403323
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2403323
Keywords
This article is cited by
-
Human germinal center transcriptional programs are de-synchronized in B cell lymphoma
Nature Immunology (2018)
-
Transformed follicular lymphoma
Annals of Hematology (2018)
-
High-risk follicular lymphomas harbour more somatic mutations including those in the AID-motif
Scientific Reports (2017)
-
Establishment of induced pluripotent stem cells from normal B cells and inducing AID expression in their differentiation into hematopoietic progenitor cells
Scientific Reports (2017)
-
Expression of activation-induced cytidine deaminase is associated with a poor prognosis of diffuse large B cell lymphoma patients treated with CHOP-based chemotherapy
Journal of Cancer Research and Clinical Oncology (2016)