Abstract
Activation-induced cytidine deaminase (AID), highly expressed in germinal center (GC)-lymphocytes, is involved in somatic hypermutation (SHM). We examined AID expression in diffuse large B-cell lymphomas (DLBCL) of germinal center B-cell (GCB)-like and activated B-cell (ABC)-like subtypes. These two types of DLBCL are characterized by high and low expression of GC-specific genes, respectively. AID expression was detected in both GCB- and ABC-like DLBCL, thus demonstrating a dissociation between AID expression and that of other GC genes. We also tested for the presence of intraclonal heterogeneity in immunoglobulin and BCL6 genes in those same tumors and in follicle center lymphomas (FCL) that transformed to DLBCL. The level of AID expression did not correlate with the presence of intraclonal sequence heterogeneity in either IgVH or BCL6. Our findings suggest that lymphomas maintain some but not all of the gene expression signatures of their normal B-cell counterparts. The fact that AID expression can be elevated without intraclonal sequence heterogeneity raises the possibility that other factors are required for SHM in these tumors. We found decreased levels of AID expression in DLBCL that evolved from FCL and which had acquired new mutations in their BCL6 genes. This dissociation suggests that AID expression and SHM may occur at the time prior to the clinical detection of transformed lymphoma.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
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 [see comments]. Nature 2000; 403: 503–511.
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.
Lossos IS, Okada CY, Tibshirani R, Warnke R, Vose JM, Greiner TC et al. Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas. Blood 2000; 95: 1797–1803.
Lossos IS, Alizadeh AA, Eisen MB, Chan WC, Brown PO, Botstein D et al. Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas. Proc Natl Acad Sci USA 2000; 97: 10209–10213.
Bahler DW, Levy R . Clonal evolution of a follicular lymphoma: evidence for antigen selection. Proc Natl Acad Sci USA 1992; 89: 6770–6774.
Muschen M, Re D, Jungnickel B, Diehl V, Rajewsky K, Kuppers R . Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction. J Exp Med 2000; 192: 1833–1840.
Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA 1998; 95: 11816–11821.
Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 2001; 412: 341–346.
Martin A, Bardwell PD, Woo CJ, Fan M, Shulman MJ, Scharff MD . Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 2002; 415: 802–806.
Martin A, Scharff MD . Somatic hypermutation of the AID transgene in B and non-B cells. Proc Natl Acad Sci USA 2002; 99: 12304–12308.
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.
Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000; 102: 553–563.
Petersen-Mahrt SK, Harris RS, Neuberger MS . AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 2002; 418: 99–103.
Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS . Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol 2002; 12: 1748–1755.
Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N et al. Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 2003; 4: 1023–1028.
Yoshikawa K, Okazaki IM, Eto T, Kinoshita K, Muramatsu M, Nagaoka H et al. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 2002; 296: 2033–2036.
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 lymphomas. Blood 2003; 101: 3574–3580.
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.
Lossos IS, Alizadeh AA, Diehn M, Warnke R, Thorstenson Y, Oefner PJ et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci USA 2002; 99: 8886–8891.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 1937–1947.
Lossos IS, Czerwinski DK, Wechser MA, Levy R . Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies. Leukemia 2003; 17: 789–795.
Zhou C, Saxon A, Zhang K . Human activation-induced cytidine deaminase is induced by IL-4 and negatively regulated by CD45: implication of CD45 as a Janus kinase phosphatase in antibody diversification. J Immunol 2003; 170: 1887–1893.
Davis RE, Brown KD, Siebenlist U, Staudt LM . Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001; 194: 1861–1874.
Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR, Chiorazzi N . Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 2003; 102: 3333–3339.
Acknowledgements
This work was supported by the developmental grant from the Sylvester Comprehensive Cancer Center and the Dwoskin Family Foundation (IL) and CA33399 and CA34233 from the USPHS-NIH (RL).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lossos, I., Levy, R. & Alizadeh, A. 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 (2004). https://doi.org/10.1038/sj.leu.2403488
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2403488
Keywords
This article is cited by
-
Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response
npj Precision Oncology (2022)
-
Activation-induced cytidine deaminase overexpression in double-hit lymphoma: potential target for novel anticancer therapy
Scientific Reports (2020)
-
AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis
Nature Communications (2018)
-
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)
-
Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential
BMC Cancer (2015)