Abstract
Pyothorax-associated lymphoma (PAL) is an Epstein–Barr virus (EBV)-associated B cell lymphoma developing in the pleural cavity affected by chronic pyothorax. To clarify the cell origin of PAL, the expression of immunoglobulin heavy (IgH) and light chains in relation to somatic hypermutations (SHMs) of rearranged Ig heavy- and light-chain variable (IgVH, IgVL) genes was examined using cell lines as well as clinical samples. SHMs without ongoing mutations of the IgVH gene were found in all PAL cell lines and clinical samples available for sequencing, indicating PAL to be derived from B cells at the postgerminal center (GC) stage of the differentiation process. They could be subdivided into post-GC cells with potentially productive IgVH genotypes (Group 1) and with sterile IgVH genotypes (Group 2). IgH expression was abrogated in Group 2 as expected and also in two cell lines in Group 1. DNA demethylation experiments with 5-aza-dC induced expression of IgH mRNA and protein in these cell lines. Most PAL cells were derived from crippled post-GC cells, which usually could not survive. Transformation of such B cells through EBV infection might provide a basis for the development of PAL with additional genetic changes.
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References
Nakatsuka S, Yao M, Hoshida Y, Yamamoto S, Iuchi K, Aozasa K . Pyothorax-associated lymphoma: a review of 106 cases. J Clin Oncol 2003; 20: 4255–4260.
Banks PM, Harris NL, Warnke RA, Gaulard PH . Lymphomas. In: Travis WD, Brambilla E, Mueller-Hermelink HK, Harris CC (eds). World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press: Lyon, 2004,pp 137–140.
Rickinson AB, Kieff E . Epstein–Barr virus.In: DM Knipe and PM Howley (eds). Fields Virology, 4th edn. Lippincott Williams and Raven: Philadelphia, 2001,pp 2575–2627.
Timms JM, Bell A, Flavell JR, Murray PG, Rickinson AB, Traverse-Glehen A et al. Target cells of Epstein–Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin’s lymphoma. Lancet 2003; 361: 217–223.
Kanzler H, Kuppers R, Hansmann ML, Rajewsky K . Hodgkin and Reed–Sternberg cells in Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 184; 1996: 1495–1505.
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.
Kuppers R, Klein U, Hansmann ML, Rajewsky K . Cellular origin of human B-cell lymphomas. N Engl J Med 1999; 341: 1520–1529.
Miwa H, Takakuwa T, Nakatsuka S, Tomita Y, Iuchi K, Aozasa K . DNA sequence of immunoglobulin heavy chain variable region gene in pyothorax-associated lymphoma. Oncology 2002; 62: 241–250.
Takakuwa T, Luo WJ, Ham MF, Mizuki M, Iuchi K, Aozasa K . Establishment and characterization of unique cell lines derived from pyothorax-associated lymphoma which develops in long-standing pyothorax and is strongly associated with Epstein–Barr virus infection. Cancer Sci 2003; 94: 858–863.
Kanno H, Yasunaga Y, Ohsawa M, Taniwaki M, Iuchi K, Naka N et al. Expression of Epstein–Barr virus latent infection genes and oncogenes in lymphoma cell lines derived from pyothorax-associated lymphoma. Int J Cancer 1996; 67: 86–94.
Daibata M, Taguchi T, Nemoto Y, Saito T, Machida H, Imai S et al. Epstein–Barr virus (EBV)-positive pyothorax-associated lymphoma (PAL): chromosomal integration of EBV in a novel CD2-positive PAL B-cell line. Br J Haematol 2002; 117: 546–557.
al Saati T, Delecluze HJ, Chittal S, Brousset P, Magaud JP, Dastugue N et al. A novel human lymphoma cell line (Deglis) with dual B/T phenotype and gene rearrangements and containing Epstein–Barr virus genomes. Blood 1992; 80: 209–216.
Gatter KC, Warnke RA . Diffuse large B-cell lymphoma.In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumors: Pathology and Genetics: Tumors of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2004,pp 171–174.
van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317.
Willis TG, Jadayel DM, Coignet LJ, Abdul-Rauf M, Treleaven JG, Catovsky D et al. Rapid molecular cloning of rearrangements of the IGHJ locus using long-distance inverse polymerase chain reaction. Blood 1997; 90: 2456–2464.
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, Tibshirani R, Narasimhan B, Levy R . The inference of antigen selection on Ig genes. J Immunol 2000; 165: 5122–5126.
Ushmsorov A, Ritz O, Hummel M, Leithauser F, Moller P, Stein H et al. Epigenetic silencing of the immunoglobulin heavy-chain gene in classical Hodgkin lymphoma-derived cell lines contributes to the loss of immunoglobulin expression. Blood 2004; 104: 3326–3334.
Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA . EBV persistence in memory B cells in vivo. Immunity 1998; 9: 395–404.
Gires O, Zimber-Strobl U, Gonnella R, Ueffing M, Marschall G, Zeidler R et al. Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule. EMBO J 1997; 16: 6131–6140.
Kilger E, Kieser A, Baumann M, Hammerschmidt W . Epstein–Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 1998; 17: 1700–1709.
Zarnegar B, He JQ, Oganesyan G, Hoffmann A, Baltimore D, Cheng G . Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways. Proc Natl Acad Sci USA 2004; 101: 8108–8113.
Alber G, Kim KM, Weiser P, Riesterer C, Carsetti R, Reth M . Molecular mimicry of the antigen receptor signalling motif by transmembrane proteins of the Epstein–Barr virus and the bovine leukaemia virus. Curr Biol 1993; 3: 333–339.
Bechtel D, Kurth J, Unkel C, Kuppers R . Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and post-transplantation lymphomas. Blood 2005; 106: 4345–4350.
Kuppers R, Rajewsky K, Zhao M, Simons G, Laumann R, Fischer R et al. Hodgkin disease: Hodgkin and Reed–Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA 1994; 91: 10962–10966.
Re D, Muschen M, Ahmadi T, Wickenhauser C, Staratschek-Jox A, Holtick U et al. Oct-2 and Bob-1 deficiency in Hodgkin and Reed–Sternberg cells. Cancer Res 2001; 61: 2080–2084.
Kuppers R, Rajewsky K, Hansmann ML . Diffuse large cell lymphomas are derived from mature B cells carrying V region genes with a high load of somatic mutation and evidence of selection for antibody expression. Eur J Immunol 1997; 27: 1398–1405.
Islam KB, Hassan MS, Engstrom PE, Hammarstrom L, Smith CI . Transcription, translation and secretion of both IgA subclasses in polyclonally activated human lymphocytes. Eur J Immunol 1990; 20: 977–982.
Acknowledgements
This study was supported by grants from the Ministry of Education, Science, Culture, and Sports, Japan (14031213, 14770073, 15026209, 15406013, 15590340, 16390105 and 18014015).
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Takakuwa, T., Tresnasari, K., Rahadiani, N. et al. Cell origin of pyothorax-associated lymphoma: a lymphoma strongly associated with Epstein–Barr virus infection. Leukemia 22, 620–627 (2008). https://doi.org/10.1038/sj.leu.2405059
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DOI: https://doi.org/10.1038/sj.leu.2405059
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