Lymphoma pp 1-25 | Cite as

Origin and Pathogenesis of B Cell Lymphomas

  • Marc Seifert
  • René Scholtysik
  • Ralf KüppersEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 971)


Immunoglobulin (Ig) gene remodeling by V(D)J recombination plays a central role in the generation of normal B cells, and somatic hypermutation and class switching of Ig genes are key processes during antigen-driven B cell differentiation. However, errors of these processes are involved in the development of B cell lymphomas. Ig locus-associated translocations of proto-oncogenes are a hallmark of many B cell malignancies. Additional transforming events include inactivating mutations in various tumor suppressor genes, and also latent infection of B cells with viruses, such as Epstein–Barr virus. Many B cell lymphomas require B cell antigen receptor expression, and in several instances chronic antigenic stimulation plays a role in sustaining tumor growth. Often, survival and proliferation signals provided by other cells in the microenvironment are a further critical factor in lymphoma development and pathophysiology. Many B cell malignancies derive from germinal center B cells, most likely because of the high proliferation rate of these cells and the high activity of mutagenic processes.

Key words

B cells B cell lymphoma Clonality Chromosomal translocation Germinal center Hodgkin’s lymphoma Immunoglobulin genes V gene recombination Somatic hypermutation 



Own work discussed in this review was supported by grants from the Deutsche Forschungsgemeinschaft (TRR60, KU1315/7-1, KU1315/8-1, GK1431), the Deutsche Krebshilfe, the Wilhelm Sander Foundation, the José Carreras Leukemia Foundation, and the BMBF (Haematosys consortium). We thank the other members of our group and Martin-Leo Hansmann for many stimulating discussions.


  1. 1.
    Tonegawa S (1983) Somatic generation of antibody diversity. Nature 302:575–581PubMedCrossRefGoogle Scholar
  2. 2.
    van Gent DC, Ramsden DA, Gellert M (1996) The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination. Cell 85:107–113PubMedCrossRefGoogle Scholar
  3. 3.
    Medina KL, Singh H (2005) Genetic networks that regulate B lymphopoiesis. Curr Opin Hematol 12:203–209PubMedCrossRefGoogle Scholar
  4. 4.
    Rajewsky K (1996) Clonal selection and learning in the antibody system. Nature 381:751–758PubMedCrossRefGoogle Scholar
  5. 5.
    Corbett SJ, Tomlinson IM, Sonnhammer EL, Buck D, Winter G (1997) Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, “minor” D segments or D–D recombination. J Mol Biol 270:587–597PubMedCrossRefGoogle Scholar
  6. 6.
    Ravetch JV, Siebenlist U, Korsmeyer S, Waldmann T, Leder P (1981) Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell 27:583–591PubMedCrossRefGoogle Scholar
  7. 7.
    Cook GP, Tomlinson IM (1995) The human immunoglobulin VH repertoire. Immunol Today 16:237–242PubMedCrossRefGoogle Scholar
  8. 8.
    Alt FW, Rathbun G, Oltz E, Taccioli G, Shinkai Y (1992) Function and control of recombination-activating gene activity. Ann N Y Acad Sci 651:277–294PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang Z (2007) VH replacement in mice and humans. Trends Immunol 28:132–137PubMedCrossRefGoogle Scholar
  10. 10.
    Tiegs SL, Russell DM, Nemazee D (1993) Receptor editing in self-reactive bone marrow B cells. J Exp Med 177:1009–1020PubMedCrossRefGoogle Scholar
  11. 11.
    Hieter PA, Maizel JV Jr, Leder P (1982) Evolution of human immunoglobulin kappa J region genes. J Biol Chem 257:1516–1522PubMedGoogle Scholar
  12. 12.
    Schäble KF, Zachau HG (1993) The variable genes of the human immunoglobulin kappa locus. Biol Chem Hoppe Seyler 374:1001–1022PubMedCrossRefGoogle Scholar
  13. 13.
    Kawasaki K, Minoshima S, Nakato E, Shibuya K, Shintani A, Schmeits JL, Wang J, Shimizu N (1997) One-megabase sequence analysis of the human immunoglobulin lambda gene locus. Genome Res 7:250–261PubMedCrossRefGoogle Scholar
  14. 14.
    Vasicek TJ, Leder P (1990) Structure and expression of the human immunoglobulin lambda genes. J Exp Med 172:609–620PubMedCrossRefGoogle Scholar
  15. 15.
    Bräuninger A, Goossens T, Rajewsky K, Küppers R (2001) Regulation of immunoglobulin light chain gene rearrangements during early B cell development in the human. Eur J Immunol 31:3631–3637PubMedCrossRefGoogle Scholar
  16. 16.
    Nadel B, Tang A, Feeney AJ (1998) V(H) replacement is unlikely to contribute significantly to receptor editing due to an ineffectual embedded recombination signal sequence. Mol Immunol 35:227–232PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang Z, Zemlin M, Wang YH, Munfus D, Huye LE, Findley HW, Bridges SL, Roth DB, Burrows PD, Cooper MD (2003) Contribution of Vh gene replacement to the primary B cell repertoire. Immunity 19:21–31PubMedCrossRefGoogle Scholar
  18. 18.
    MacLennan IC (1994) Germinal centers. Annu Rev Immunol 12:117–139PubMedCrossRefGoogle Scholar
  19. 19.
    Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, Cyster JG (2004) Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 5:943–952PubMedCrossRefGoogle Scholar
  20. 20.
    Hauser AE, Junt T, Mempel TR, Sneddon MW, Kleinstein SH, Henrickson SE, von Andrian UH, Shlomchik MJ, Haberman AM (2007) Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26:655–667PubMedCrossRefGoogle Scholar
  21. 21.
    Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, Kosco-Vilbois MH, Dustin ML, Nussenzweig MC (2007) In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446:83–87PubMedCrossRefGoogle Scholar
  22. 22.
    Küppers R, Zhao M, Hansmann ML, Rajewsky K (1993) Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 12:4955–4967PubMedGoogle Scholar
  23. 23.
    Goossens T, Klein U, Küppers R (1998) Frequent occurrence of deletions and duplications during somatic hypermutation: Implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci U S A 95:2463–2468PubMedCrossRefGoogle Scholar
  24. 24.
    Pavri R, Nussenzweig MC (2011) AID targeting in antibody diversity. Adv Immunol 110:1–26PubMedCrossRefGoogle Scholar
  25. 25.
    Neuberger MS (2008) Antibody diversification by somatic mutation: from Burnet onwards. Immunol Cell Biol 86:124–132PubMedCrossRefGoogle Scholar
  26. 26.
    Di Noia JM, Neuberger MST (2007) Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 76:1–22PubMedCrossRefGoogle Scholar
  27. 27.
    Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L, Chaganti RSK, Klein U, Küppers R, Rajewsky K, Dalla-Favera R (1998) BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci U S A 95:11816–11821PubMedCrossRefGoogle Scholar
  28. 28.
    Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG (2008) Two levels of protection for the B cell genome during somatic hypermutation. Nature 451:841–845PubMedCrossRefGoogle Scholar
  29. 29.
    Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC (1989) Mechanism of antigen-driven selection in germinal centres. Nature 342:929–931PubMedCrossRefGoogle Scholar
  30. 30.
    Manis JP, Tian M, Alt FW (2002) Mechanism and control of class-switch recombination. Trends Immunol 23:31–39PubMedCrossRefGoogle Scholar
  31. 31.
    Klein U, Rajewsky K, Küppers R (1998) Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med 188:1679–1689PubMedCrossRefGoogle Scholar
  32. 32.
    Seifert M, Küppers R (2009) Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation. J Exp Med 206:2659–2669PubMedCrossRefGoogle Scholar
  33. 33.
    Klein U, Dalla-Favera R (2008) Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 8:22–33PubMedCrossRefGoogle Scholar
  34. 34.
    McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L (2012) Molecular programming of B cell memory. Nat Rev Immunol 12:24–34Google Scholar
  35. 35.
    Manz RA, Hauser AE, Hiepe F, Radbruch A (2005) Maintenance of serum antibody levels. Annu Rev Immunol 23:367–386PubMedCrossRefGoogle Scholar
  36. 36.
    Han JH, Akira S, Calame K, Beutler B, Selsing E, Imanishi-Kari T (2007) Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors. Immunity 27:64–75PubMedCrossRefGoogle Scholar
  37. 37.
    Mond JJ, Lees A, Snapper CM (1995) T cell-independent antigens type 2. Annu Rev Immunol 13:655–692PubMedCrossRefGoogle Scholar
  38. 38.
    Toellner KM, Jenkinson WE, Taylor DR, Khan M, Sze DM, Sansom DM, Vinuesa CG, MacLennan IC (2002) Low-level hypermutation in T cell-independent germinal centers compared with high mutation rates associated with T cell-dependent germinal centers. J Exp Med 195:383–389PubMedCrossRefGoogle Scholar
  39. 39.
    Küppers R (2005) Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5:251–262PubMedCrossRefGoogle Scholar
  40. 40.
    de Jong D (2005) Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J Clin Oncol 23:6358–6363PubMedCrossRefGoogle Scholar
  41. 41.
    Bende RJ, Smit LA, van Noesel CJ (2007) Molecular pathways in follicular lymphoma. Leukemia 21:18–29PubMedCrossRefGoogle Scholar
  42. 42.
    Küppers R, Klein U, Hansmann M-L, Rajewsky K (1999) Cellular origin of human B-cell lymphomas. N Engl J Med 341:1520–1529PubMedCrossRefGoogle Scholar
  43. 43.
    Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511PubMedCrossRefGoogle Scholar
  44. 44.
    Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937–1947PubMedCrossRefGoogle Scholar
  45. 45.
    Lossos IS, Alizadeh AA, Eisen MB, Chan WC, Brown PO, Botstein D, Staudt LM, Levy R (2000) 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 U S A 97:10209–10213PubMedCrossRefGoogle Scholar
  46. 46.
    Küppers R (2009) The biology of Hodgkin’s lymphoma. Nat Rev Cancer 9:15–27PubMedCrossRefGoogle Scholar
  47. 47.
    Kanzler H, Küppers R, Hansmann ML, Rajewsky K (1996) 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 184:1495–1505PubMedCrossRefGoogle Scholar
  48. 48.
    Küppers R, Rajewsky K, Zhao M, Simons G, Laumann R, Fischer R, Hansmann ML (1994) 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 U S A 91:10962–10966PubMedCrossRefGoogle Scholar
  49. 49.
    Küppers R, Dalla-Favera R (2001) Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20:5580–5594PubMedCrossRefGoogle Scholar
  50. 50.
    Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Küppers R, Dalla-Favera R (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412:341–346PubMedCrossRefGoogle Scholar
  51. 51.
    Jäger U, Bocskor S, Le T, Mitterbauer G, Bolz I, Chott A, Kneba M, Mannhalter C, Nadel B (2000) Follicular lymphomas’ BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation. Blood 95:3520–3529PubMedGoogle Scholar
  52. 52.
    Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM (1985) The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229:1390–1393PubMedCrossRefGoogle Scholar
  53. 53.
    Dalla-Favera R, Martinotti S, Gallo RC, Erikson J, Croce CM (1983) Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 219:963–967PubMedCrossRefGoogle Scholar
  54. 54.
    Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S, Aaronson S, Leder P (1982) Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 79:7837–7841PubMedCrossRefGoogle Scholar
  55. 55.
    Vaandrager JW, Schuuring E, Zwikstra E, de Boer CJ, Kleiverda KK, van Krieken JH, Kluin-Nelemans HC, van Ommen GJ, Raap AK, Kluin PM (1996) Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell lymphoma by multicolor DNA fiber fluorescence in situ hybridization. Blood 88:1177–1182PubMedGoogle Scholar
  56. 56.
    Baron BW, Nucifora G, McCabe N, Espinosa R 3rd, Le Beau MM, McKeithan TW (1993) Identification of the gene associated with the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas. Proc Natl Acad Sci U S A 90:5262–5266PubMedCrossRefGoogle Scholar
  57. 57.
    Wlodarska I, Nooyen P, Maes B, Martin-Subero JI, Siebert R, Pauwels P, De Wolf-Peeters C, Hagemeijer A (2003) Frequent occurrence of BCL6 rearrangements in nodular lymphocyte predominance Hodgkin lymphoma but not in classical Hodgkin lymphoma. Blood 101:706–710PubMedCrossRefGoogle Scholar
  58. 58.
    Ye BH, Rao PH, Chaganti RS, Dalla-Favera R (1993) Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res 53:2732–2735PubMedGoogle Scholar
  59. 59.
    Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P (1999) The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93:3601–3609PubMedGoogle Scholar
  60. 60.
    Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476:298–303PubMedCrossRefGoogle Scholar
  61. 61.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, Kasper LH, Lerach S, Tang H, Ma J, Rossi D, Chadburn A, Murty VV, Mullighan CG, Gaidano G, Rabadan R, Brindle PK, Dalla-Favera R (2011) Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471:189–195PubMedCrossRefGoogle Scholar
  62. 62.
    Ammerpohl O, Haake A, Pellissery S, Giefing M, Richter J, Balint B, Kulis M, Le J, Bibikova M, Drexler HG, Seifert M, Shaknovic R, Korn B, Küppers R, Martin-Subero JI, Siebert R (2011) Array-based DNA methylation analysis in classical Hodgkin lymphoma reveals new insights into the mechanisms underlying silencing of B cell-specific genes. Leukemia 26:185–188PubMedCrossRefGoogle Scholar
  63. 63.
    Martin-Subero JI, Kreuz M, Bibikova M, Bentink S, Ammerpohl O, Wickham-Garcia E, Rosolowski M, Richter J, Lopez-Serra L, Ballestar E, Berger H, Agirre X, Bernd HW, Calvanese V, Cogliatti SB, Drexler HG, Fan JB, Fraga MF, Hansmann ML, Hummel M, Klapper W, Korn B, Küppers R, Macleod RA, Moller P, Ott G, Pott C, Prosper F, Rosenwald A, Schwaenen C, Schubeler D, Seifert M, Sturzenhofecker B, Weber M, Wessendorf S, Loeffler M, Trümper L, Stein H, Spang R, Esteller M, Barker D, Hasenclever D, Siebert R (2009) New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood 113:2488–2497PubMedCrossRefGoogle Scholar
  64. 64.
    Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Campioni D, Minotto C, Agostini P, Milani R, Bullrich F, Negrini M, Croce C, Castoldi G (1999) 13q14 deletion in non-Hodgkin’s lymphoma: correlation with clinicopathologic features. Haematologica 84:589–593PubMedGoogle Scholar
  65. 65.
    Kuehl WM, Bergsagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2:175–187PubMedCrossRefGoogle Scholar
  66. 66.
    Liu Y, Hermanson M, Grander D, Merup M, Wu X, Heyman M, Rasool O, Juliusson G, Gahrton G, Detlofsson R, Nikiforova N, Buys C, Soderhall S, Yankovsky N, Zabarovsky E, Einhorn S (1995) 13q deletions in lymphoid malignancies. Blood 86:1911–1915PubMedGoogle Scholar
  67. 67.
    Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, Ambesi-Impiombato A, Califano A, Migliazza A, Bhagat G, Dalla-Favera R (2010) The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17:28–40PubMedCrossRefGoogle Scholar
  68. 68.
    Carbone A, Gloghini A (2008) KSHV/HHV8-associated lymphomas. Br J Haematol 140:13–24PubMedGoogle Scholar
  69. 69.
    Küppers R (2003) B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol 3:801–812PubMedCrossRefGoogle Scholar
  70. 70.
    Kilger E, Kieser A, Baumann M, Hammerschmidt W (1998) Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 17:1700–1709PubMedCrossRefGoogle Scholar
  71. 71.
    Bechtel D, Kurth J, Unkel C, Küppers R (2005) Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 106:4345–4350PubMedCrossRefGoogle Scholar
  72. 72.
    Mancao C, Hammerschmidt W (2007) Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110:3715–3721PubMedCrossRefGoogle Scholar
  73. 73.
    Bräuninger A, Schmitz R, Bechtel D, Renné C, Hansmann M-L, Küppers R (2006) Molecular biology of Hodgkin and Reed/Sternberg cells in Hodgkin’s lymphoma. Int J Cancer 118:1853–1861PubMedCrossRefGoogle Scholar
  74. 74.
    Quinn ER, Chan CH, Hadlock KG, Foung SK, Flint M, Levy S (2001) The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis. Blood 98:3745–3749PubMedCrossRefGoogle Scholar
  75. 75.
    Machida K, Cheng KT, Sung VM, Lee KJ, Levine AM, Lai MM (2004) Hepatitis C virus infection activates the immunologic (type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. J Virol 78:8835–8843PubMedCrossRefGoogle Scholar
  76. 76.
    Machida K, Cheng KT, Sung VM, Shimodaira S, Lindsay KL, Levine AM, Lai MY, Lai MM (2004) Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A 101:4262–4267PubMedCrossRefGoogle Scholar
  77. 77.
    Lacroix A, Collot-Teixeira S, Mardivirin L, Jaccard A, Petit B, Piguet C, Sturtz F, Preux PM, Bordessoule D, Ranger-Rogez S (2010) Involvement of human herpesvirus-6 variant B in classic Hodgkin’s lymphoma via DR7 oncoprotein. Clin Cancer Res 16:4711–4721PubMedCrossRefGoogle Scholar
  78. 78.
    Maggio E, Benharroch D, Gopas J, Dittmer U, Hansmann ML, Küppers R (2007) Absence of measles virus genome and transcripts in Hodgkin-Reed/Sternberg cells of a cohort of Hodgkin lymphoma patients. Int J Cancer 121:448–453PubMedCrossRefGoogle Scholar
  79. 79.
    Johnson PW, Watt SM, Betts DR, Davies D, Jordan S, Norton AJ, Lister TA (1993) Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. Blood 82:1848–1857PubMedGoogle Scholar
  80. 80.
    Umetsu DT, Esserman L, Donlon TA, DeKruyff RH, Levy R (1990) Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones. J Immunol 144:2550–2557PubMedGoogle Scholar
  81. 81.
    Zhu D, McCarthy H, Ottensmeier CH, Johnson P, Hamblin TJ, Stevenson FK (2002) Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood 99:2562–2568PubMedCrossRefGoogle Scholar
  82. 82.
    Coelho V, Krysov S, Ghaemmaghami AM, Emara M, Potter KN, Johnson P, Packham G, Martinez-Pomares L, Stevenson FK (2010) Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc Natl Acad Sci U S A 107:18587–18592PubMedCrossRefGoogle Scholar
  83. 83.
    Schmid C, Isaacson PG (1994) Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. Histopathology 24:445–451PubMedCrossRefGoogle Scholar
  84. 84.
    Ghia P, Strola G, Granziero L, Geuna M, Guida G, Sallusto F, Ruffing N, Montagna L, Piccoli P, Chilosi M, Caligaris-Cappio F (2002) Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22. Eur J Immunol 32:1403–1413PubMedCrossRefGoogle Scholar
  85. 85.
    Buske C, Gogowski G, Schreiber K, Rave-Frank M, Hiddemann W, Wormann B (1997) Stimulation of B-chronic lymphocytic leukemia cells by murine fibroblasts, IL-4, anti-CD40 antibodies, and the soluble CD40 ligand. Exp Hematol 25:329–337PubMedGoogle Scholar
  86. 86.
    Chu CC, Catera R, Zhang L, Didier S, Agagnina BM, Damle RN, Kaufman MS, Kolitz JE, Allen SL, Rai KR, Chiorazzi N (2010) Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood 115:3907–3915PubMedCrossRefGoogle Scholar
  87. 87.
    Herve M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, Meffre E (2005) Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest 115:1636–1643PubMedCrossRefGoogle Scholar
  88. 88.
    Bende RJ, Aarts WM, Riedl RG, de Jong D, Pals ST, van Noesel CJM (in press) Immunoglobulins of B-cell non Hodgkin’s lymphomas: musosa-associated lymphoid tissue lymphomas express a distinctive repertoire with frequent rheumatoid factor reactivity. J Exp Med 201Google Scholar
  89. 89.
    Hussel T, Isaacson PG, Crabtree JE, Spencer J (1996) Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol 178:122–127CrossRefGoogle Scholar
  90. 90.
    Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, Isaacson PG (1993) Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori. Lancet 342:575–577PubMedCrossRefGoogle Scholar
  91. 91.
    Hermine O, Lefrere F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, Delmas B, Valensi F, Cacoub P, Brechot C, Varet B, Troussard X (2002) Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347:89–94PubMedCrossRefGoogle Scholar
  92. 92.
    Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN, Vickers MA (2004) Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:1755–1762PubMedCrossRefGoogle Scholar
  93. 93.
    Chemnitz JM, Eggle D, Driesen J, Classen S, Riley JL, Debey-Pascher S, Beyer M, Popov A, Zander T, Schultze JL (2007) RNA fingerprints provide direct evidence for the inhibitory role of TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma. Blood 110:3226–3233PubMedCrossRefGoogle Scholar
  94. 94.
    Gandhi MK, Moll G, Smith C, Dua U, Lambley E, Ramuz O, Gill D, Marlton P, Seymour JF, Khanna R (2007) Galectin-1 mediated suppression of Epstein-Barr virus specific T-cell immunity in classic Hodgkin lymphoma. Blood 110:1326–1329PubMedCrossRefGoogle Scholar
  95. 95.
    Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J, Chen W, Kutok JL, Rabinovich GA, Shipp MA (2007) The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A 104:13134–13139PubMedCrossRefGoogle Scholar
  96. 96.
    Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, Kondo T, Ohmori K, Kurata M, Hayashi T, Uchiyama T (2008) PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 111:3220–3224PubMedCrossRefGoogle Scholar
  97. 97.
    Shaffer AL, Young RM, Staudt LM (2012) Pathogenesis of human B cell lymphomas. Annu Rev Immunol 30:565–610PubMedCrossRefGoogle Scholar
  98. 98.
    Camacho E, Hernandez L, Hernandez S, Tort F, Bellosillo B, Bea S, Bosch F, Montserrat E, Cardesa A, Fernandez PL, Campo E (2002) ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances. Blood 99:238–244PubMedCrossRefGoogle Scholar
  99. 99.
    Schaffner C, Idler I, Stilgenbauer S, Dohner H, Lichter P (2000) Mantle cell lymphoma is characterized by inactivation of the ATM gene. Proc Natl Acad Sci U S A 97:2773–2778PubMedCrossRefGoogle Scholar
  100. 100.
    Kridel R, Meissner B, Rogic S, Boyle M, Telenius A, Woolcock B, Gunawardana J, Jenkins C, Cochrane C, Ben-Neriah S, Tan K, Morin RD, Opat S, Sehn LH, Connors JM, Marra MA, Weng AP, Steidl C, Gascoyne RD (2012) Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119:1963–1971PubMedCrossRefGoogle Scholar
  101. 101.
    Jares P, Colomer D, Campo E (2007) Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 7:750–762PubMedCrossRefGoogle Scholar
  102. 102.
    Chanudet E, Huang Y, Ichimura K, Dong G, Hamoudi RA, Radford J, Wotherspoon AC, Isaacson PG, Ferry J, Du MQ (2010) A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma. Leukemia 24:483–487PubMedCrossRefGoogle Scholar
  103. 103.
    Schaffner C, Stilgenbauer S, Rappold GA, Dohner H, Lichter P (1999) Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 94:748–753PubMedGoogle Scholar
  104. 104.
    Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd PJ, Moss PA, Taylor AM (1999) Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 353:26–29PubMedCrossRefGoogle Scholar
  105. 105.
    Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, Grunn A, Fangazio M, Capello D, Monti S, Cresta S, Gargiulo E, Forconi F, Guarini A, Arcaini L, Paulli M, Laurenti L, Larocca LM, Marasca R, Gattei V, Oscier D, Bertoni F, Mullighan CG, Foa R, Pasqualucci L, Rabadan R, Dalla-Favera R, Gaidano G (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 208:1389–1401PubMedCrossRefGoogle Scholar
  106. 106.
    Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Bea S, Gonzalez-Diaz M, Bassaganyas L, Baumann T, Juan M, Lopez-Guerra M, Colomer D, Tubio JM, Lopez C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernandez JM, Puente DA, Freije JM, Velasco G, Gutierrez-Fernandez A, Costa D, Carrio A, Guijarro S, Enjuanes A, Hernandez L, Yague J, Nicolas P, Romeo-Casabona CM, Himmelbauer H, Castillo E, Dohm JC, de Sanjose S, Piris MA, de Alava E, San Miguel J, Royo R, Gelpi JL, Torrents D, Orozco M, Pisano DG, Valencia A, Guigo R, Bayes M, Heath S, Gut M, Klatt P, Marshall J, Raine K, Stebbings LA, Futreal PA, Stratton MR, Campbell PJ, Gut I, Lopez-Guillermo A, Estivill X, Montserrat E, Lopez-Otin C, Campo E (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475:101–105PubMedCrossRefGoogle Scholar
  107. 107.
    Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW, Magrath IT, Knowles DM, Dalla-Favera R (1991) p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 88:5413–5417PubMedCrossRefGoogle Scholar
  108. 108.
    Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L, Ramsay AJ, Bea S, Pinyol M, Martinez-Trillos A, Lopez-Guerra M, Colomer D, Navarro A, Baumann T, Aymerich M, Rozman M, Delgado J, Gine E, Hernandez JM, Gonzalez-Diaz M, Puente DA, Velasco G, Freije JM, Tubio JM, Royo R, Gelpi JL, Orozco M, Pisano DG, Zamora J, Vazquez M, Valencia A, Himmelbauer H, Bayes M, Heath S, Gut M, Gut I, Estivill X, Lopez-Guillermo A, Puente XS, Campo E, Lopez-Otin C (2011) Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 44:47–52PubMedCrossRefGoogle Scholar
  109. 109.
    Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, Messina M, Fangazio M, Vaisitti T, Monti S, Chiaretti S, Guarini A, Del Giudice I, Cerri M, Cresta S, Deambrogi C, Gargiulo E, Gattei V, Forconi F, Bertoni F, Deaglio S, Rabadan R, Pasqualucci L, Foa R, Dalla-Favera R, Gaidano G (2011) Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 118:6904–6908PubMedCrossRefGoogle Scholar
  110. 110.
    Gronbaek K, Straten PT, Ralfkiaer E, Ahrenkiel V, Andersen MK, Hansen NE, Zeuthen J, Hou-Jensen K, Guldberg P (1998) Somatic Fas mutations in non-Hodgkin’s lymphoma: association with extranodal disease and autoimmunity. Blood 92:3018–3024PubMedGoogle Scholar
  111. 111.
    Weiss LM, Warnke RA, Sklar J, Cleary ML (1987) Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 317:1185–1189PubMedCrossRefGoogle Scholar
  112. 112.
    Gronbaek K, Worm J, Ralfkiaer E, Ahrenkiel V, Hokland P, Guldberg P (2002) ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma. Blood 100:1430–1437PubMedCrossRefGoogle Scholar
  113. 113.
    Ladanyi M, Offit K, Jhanwar SC, Filippa DA, Chaganti RS (1991) MYC rearrangement and translocations involving band 8q24 in diffuse large cell lymphomas. Blood 77:1057–1063PubMedGoogle Scholar
  114. 114.
    Koduru PR, Raju K, Vadmal V, Menezes G, Shah S, Susin M, Kolitz J, Broome JD (1997) Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin’s lymphoma. Blood 90:4078–4091PubMedGoogle Scholar
  115. 115.
    Moller MB, Ino Y, Gerdes AM, Skjodt K, Louis DN, Pedersen NT (1999) Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. Leukemia 13:453–459PubMedCrossRefGoogle Scholar
  116. 116.
    Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A, Nandula SV, Aster JC, Murty VV, Shipp MA, Dalla-Favera R (2006) Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med 203:311–317PubMedCrossRefGoogle Scholar
  117. 117.
    Jardin F, Jais JP, Molina TJ, Parmentier F, Picquenot JM, Ruminy P, Tilly H, Bastard C, Salles GA, Feugier P, Thieblemont C, Gisselbrecht C, de Reynies A, Coiffier B, Haioun C, Leroy K (2010) Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study. Blood 116:1092–1104PubMedCrossRefGoogle Scholar
  118. 118.
    Honma K, Tsuzuki S, Nakagawa M, Tagawa H, Nakamura S, Morishima Y, Seto M (2009) TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood 114:2467–2475PubMedCrossRefGoogle Scholar
  119. 119.
    Melzner I, Bucur AJ, Bruderlein S, Dorsch K, Hasel C, Barth TF, Leithäuser F, Möller P (2005) Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105:2535–2542PubMedCrossRefGoogle Scholar
  120. 120.
    Rossi D, Cerri M, Capello D, Deambrogi C, Berra E, Franceschetti S, Alabiso O, Gloghini A, Paulli M, Carbone A, Pileri SA, Pasqualucci L, Gaidano G (2005) Aberrant somatic hypermutation in primary mediastinal large B-cell lymphoma. Leukemia 19:2363–2366PubMedCrossRefGoogle Scholar
  121. 121.
    Ritz O, Guiter C, Castellano F, Dorsch K, Melzner J, Jais JP, Dubois G, Gaulard P, Möller P, Leroy K (2009) Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood 114:1236–1242PubMedCrossRefGoogle Scholar
  122. 122.
    Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G, Klapper W, Vater I, Giefing M, Gesk S, Stanelle J, Siebert R, Küppers R (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206:981–989PubMedCrossRefGoogle Scholar
  123. 123.
    Cinti C, Leoncini L, Nyongo A, Ferrari F, Lazzi S, Bellan C, Vatti R, Zamparelli A, Cevenini G, Tosi GM, Claudio PP, Maraldi NM, Tosi P, Giordano A (2000) Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt’s lymphoma subtypes. Am J Pathol 156:751–760PubMedCrossRefGoogle Scholar
  124. 124.
    Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT (1999) Mutations in the IkBa gene in Hodgkin’s disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 18:3063–3070PubMedCrossRefGoogle Scholar
  125. 125.
    Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dörken B, Scheidereit C (1999) Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 18:943–953PubMedCrossRefGoogle Scholar
  126. 126.
    Jungnickel B, Staratschek-Jox A, Bräuninger A, Spieker T, Wolf J, Diehl V, Hansmann ML, Rajewsky K, Küppers R (2000) Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin’s lymphoma. J Exp Med 191:395–402PubMedCrossRefGoogle Scholar
  127. 127.
    Martin-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B, Grote W, Novo FJ, Calasanz MJ, Hansmann ML, Dyer MJ, Siebert R (2002) Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 99:1474–1477PubMedCrossRefGoogle Scholar
  128. 128.
    Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Dohner K, Bommert K, Stein H, Dörken B (2003) Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol 201:413–420PubMedCrossRefGoogle Scholar
  129. 129.
    Schmitz R, Stanelle J, Hansmann ML, Küppers R (2009) Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma. Annu Rev Pathol 4:151–174PubMedCrossRefGoogle Scholar
  130. 130.
    Müschen M, Re D, Brauninger A, Wolf J, Hansmann ML, Diehl V, Küppers R, Rajewsky K (2000) Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells. Cancer Res 60:5640–5643PubMedGoogle Scholar
  131. 131.
    Otto C, Giefing M, Massow A, Vater I, Gesk S, Schlesner M, Richter J, Klapper W, Hansmann M-L, Siebert R, Küppers R (2012) Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Haematol 157:702–708Google Scholar
  132. 132.
    Steidl C, Telenius A, Shah SP, Farinha P, Barclay L, Boyle M, Connors JM, Horsman DE, Gascoyne RD (2010) Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 116:418–427PubMedCrossRefGoogle Scholar
  133. 133.
    Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, Mattfeldt T, Barth TF, Möller P (2006) Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 25:2679–2684PubMedCrossRefGoogle Scholar
  134. 134.
    Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martinez P, Piris MA (1999) 7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphoma. Am J Pathol 154:1583–1589PubMedCrossRefGoogle Scholar
  135. 135.
    Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M, Price H, Karran L, Majekodunmi O, Wlodarska I, Pan L, Crook T, Hamoudi R, Isaacson PG, Dyer MJ (1999) Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96:35–45PubMedCrossRefGoogle Scholar
  136. 136.
    Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L, Rakestraw KM, Naeve CW, Beckmann G, Weisenburger DD, Sanger WG, Nowotny H, Vesely M, Callet-Bauchu E, Salles G, Dixit VM, Rosenthal A, Schlegelberger B, Morris SW (1999) Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 22:63–68PubMedCrossRefGoogle Scholar
  137. 137.
    Takino H, Okabe M, Li C, Ohshima K, Yoshino T, Nakamura S, Ueda R, Eimoto T, Inagaki H (2005) p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis. Mod Pathol 18:1187–1192PubMedCrossRefGoogle Scholar
  138. 138.
    Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A (2003) T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 101:2335–2339PubMedCrossRefGoogle Scholar
  139. 139.
    Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A (2005) T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 19:652–658PubMedGoogle Scholar
  140. 140.
    Iida S, Rao PH, Nallasivam P, Hibshoosh H, Butler M, Louie DC, Dyomin V, Ohno H, Chaganti RS, Dalla-Favera R (1996) The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. Blood 88:4110–4117PubMedGoogle Scholar
  141. 141.
    Avet-Loiseau H, Li JY, Facon T, Brigaudeau C, Morineau N, Maloisel F, Rapp MJ, Talmant P, Trimoreau F, Jaccard A, Harousseau JL, Bataille R (1998) High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. Cancer Res 58:5640–5645PubMedGoogle Scholar
  142. 142.
    Landowski TH, Qu N, Buyuksal I, Painter JS, Dalton WS (1997) Mutations in the Fas antigen in patients with multiple myeloma. Blood 90:4266–4270PubMedGoogle Scholar
  143. 143.
    Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, Dewald G, Kirsch IR, Bergsagel PL, Kuehl WM (2000) Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci U S A 97:228–233PubMedCrossRefGoogle Scholar
  144. 144.
    Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM, Bergsagel PL (1997) Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16:260–264PubMedCrossRefGoogle Scholar
  145. 145.
    Liu P, Leong T, Quam L, Billadeau D, Kay NE, Greipp P, Kyle RA, Oken MM, Van Ness B (1996) Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 88:2699–2706PubMedGoogle Scholar
  146. 146.
    Chesi M, Bergsagel PL, Shonukan OO, Martelli ML, Brents LA, Chen T, Schrock E, Ried T, Kuehl WM (1998) Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457–4463PubMedGoogle Scholar
  147. 147.
    Munshi NC, Avet-Loiseau H (2011) Genomics in multiple myeloma. Clin Cancer Res 17:1234–1242PubMedCrossRefGoogle Scholar
  148. 148.
    Dunn-Walters DK, Isaacson PG, Spencer J (1995) Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med 182:559–566PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Institute of Cell Biology (Cancer Research), Medical SchoolUniversity of Duisburg-EssenEssenGermany

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