Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Leading Article
  • Published:

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

Abstract

In a European BIOMED-2 collaborative study, multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged immunoglobulin (Ig) and T-cell receptor (TCR) genes and the chromosome aberrations t(11;14) and t(14;18). This has resulted in 107 different primers in only 18 multiplex PCR tubes: three VH–JH, two DH–JH, two Ig kappa (IGK), one Ig lambda (IGL), three TCR beta (TCRB), two TCR gamma (TCRG), one TCR delta (TCRD), three BCL1-Ig heavy chain (IGH), and one BCL2-IGH. The PCR products of Ig/TCR genes can be analyzed for clonality assessment by heteroduplex analysis or GeneScanning. The detection rate of clonal rearrangements using the BIOMED-2 primer sets is unprecedentedly high. This is mainly based on the complementarity of the various BIOMED-2 tubes. In particular, combined application of IGH (VH–JH and DH–JH) and IGK tubes can detect virtually all clonal B-cell proliferations, even in B-cell malignancies with high levels of somatic mutations. The contribution of IGL gene rearrangements seems limited. Combined usage of the TCRB and TCRG tubes detects virtually all clonal T-cell populations, whereas the TCRD tube has added value in case of TCRγδ+ T-cell proliferations. The BIOMED-2 multiplex tubes can now be used for diagnostic clonality studies as well as for the identification of PCR targets suitable for the detection of minimal residual disease.

This is a preview of subscription content, access via your institution

Access options

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 4
Figure 5
Figure 6
Figure 6
Figure 7
Figure 8
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14

References

  1. van Dongen JJM, Wolvers-Tettero ILM . Analysis of immunoglobulin and T cell receptor genes. Part II: possibilities and limitations in the diagnosis and management of lymphoproliferative diseases and related disorders. Clin Chim Acta 1991; 198: 93–174.

    Article  CAS  PubMed  Google Scholar 

  2. Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001.

    Google Scholar 

  3. Tonegawa S . Somatic generation of antibody diversity. Nature 1983; 302: 575–581.

    Article  CAS  PubMed  Google Scholar 

  4. Davis MM, Björkman PJ . T-cell antigen receptor genes and T-cell recognition. Nature 1988; 334: 395–402.

    Article  CAS  PubMed  Google Scholar 

  5. van Dongen JJM, Szczepanski T, Adriaansen HJ . Immunobiology of leukemia. In: Henderson ES, Lister TA, Greaves MF (eds) Leukemia. Philadelphia: WB Saunders Company, 2002, pp 85–129.

    Google Scholar 

  6. Szczepanski T, Pongers-Willemse MJ, Langerak AW, van Dongen JJM . Unusual immunoglobulin and T-cell receptor gene rearrangement patterns in acute lymphoblastic leukemias. Curr Top Microbiol Immunol 1999; 246: 205–215.

    CAS  PubMed  Google Scholar 

  7. Küppers R, Klein U, Hansmann ML, Rajewsky K . Cellular origin of human B-cell lymphomas. N Engl J Med 1999; 341: 1520–1529.

    Article  PubMed  Google Scholar 

  8. Smith BR, Weinberg DS, Robert NJ, Towle M, Luther E, Pinkus GS et al. Circulating monoclonal B lymphocytes in non-Hodgkin's lymphoma. N Engl J Med 1984; 311: 1476–1481.

    Article  CAS  PubMed  Google Scholar 

  9. Letwin BW, Wallace PK, Muirhead KA, Hensler GL, Kashatus WH, Horan PK . An improved clonal excess assay using flow cytometry and B-cell gating. Blood 1990; 75: 1178–1185.

    CAS  PubMed  Google Scholar 

  10. Fukushima PI, Nguyen PK, O'Grady P, Stetler-Stevenson M . Flow cytometric analysis of kappa and lambda light chain expression in evaluation of specimens for B-cell neoplasia. Cytometry 1996; 26: 243–252.

    Article  CAS  PubMed  Google Scholar 

  11. McCoy Jr JP, Overton WR, Schroeder K, Blumstein L, Donaldson MH . Immunophenotypic analysis of the T cell receptor V beta repertoire in CD4+ and CD8+ lymphocytes from normal peripheral blood. Cytometry 1996; 26: 148–153.

    Article  CAS  PubMed  Google Scholar 

  12. van Dongen JJM, van den Beemd MWM, Schellekens M, Wolvs-Tettero ILM, Langerak AW, Groeneveld K . Analysis of malignant T cells with the Vβ antibody panel. Immunologist 1996; 4: 37–40.

    CAS  Google Scholar 

  13. Van den Beemd MWM, Boor PPC, Van Lochem EG, Hop WCJ, Langerak AW, Wolvers-Tettero ILM et al. Flow ctometric analysis of the Vβ repertoire in healthy controls. Cytometry 2000; 40: 336–345.

    Article  CAS  PubMed  Google Scholar 

  14. Lima M, Almeida J, Santos AH, dos Anjos Teixeira M, Alguero MC, Queiros ML et al. Immunophenotypic analysis of the TCR-Vbeta repertoire in 98 persistent expansions of CD3(+)/TCR-alphabeta(+) large granular lymphocytes: utility in assessing clonality and insights into the pathogenesis of the disease. Am J Pathol 2001; 159: 1861–1868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Langerak AW, Wolvers-Tettero ILM, van den Beemd MWM, van Wering ER, Ludwig W-D, Hählen K et al. Immunophenotypic and immunogenotypic characteristics of TCRγδ+ T cell acute lymphoblastic leukemia. Leukemia 1999; 13: 206–214.

    Article  CAS  PubMed  Google Scholar 

  16. Langerak AW, van Den Beemd R, Wolvers-Tettero ILM, Boor PP, van Lochem EG, Hooijkaas H et al. Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCRalphabeta T-cell proliferations. Blood 2001; 98: 165–173.

    Article  CAS  PubMed  Google Scholar 

  17. Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran Jr TP . The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 1997; 89: 256–260.

    CAS  PubMed  Google Scholar 

  18. Triebel F, Faure F, Graziani M, Jitsukawa S, Lefranc MP, Hercend T . A unique V–J–C-rearranged gene encodes a gamma protein expressed on the majority of CD3+ T cell receptor-alpha/beta-circulating lymphocytes. J Exp Med 1988; 167: 694–699.

    Article  CAS  PubMed  Google Scholar 

  19. Breit TM, Wolvers-Tettero IL, van Dongen JJ . Unique selection determinant in polyclonal V delta 2–J delta 1 junctional regions of human peripheral gamma delta T lymphocytes. J Immunol 1994; 152: 2860–2864.

    CAS  PubMed  Google Scholar 

  20. Breit TM, Wolvers-Tettero ILM, Hählen K, Van Wering ER, van Dongen JJM . Limited combinatorial repertoire of γδ T-cell receptors expressed by T-cell acute lymphoblastic leukemias. Leukemia 1991; 5: 116–124.

    CAS  PubMed  Google Scholar 

  21. van Dongen JJM, Wolvers-Tettero ILM . Analysis of immunoglobulin and T cell receptor genes. Part I: basic and technical aspects. Clin Chim Acta 1991; 198: 1–91.

    Article  CAS  PubMed  Google Scholar 

  22. Beishuizen A, Verhoeven MA, Mol EJ, Breit TM, Wolvers-Tettero ILM, van Dongen JJM . Detection of immunoglobulin heavy-chain gene rearrangements by Southern blot analysis: recommendations for optimal results. Leukemia 1993; 7: 2045–2053.

    CAS  PubMed  Google Scholar 

  23. Breit TM, Wolvers-Tettero ILM, Beishuizen A, Verhoeven M-AJ, van Wering ER, van Dongen JJM . Southern blot patterns, frequencies and junctional diversity of T-cell receptor δ gene rearrangements in acute lymphoblastic leukemia. Blood 1993; 82: 3063–3074.

    CAS  PubMed  Google Scholar 

  24. Beishuizen A, Verhoeven MA, Mol EJ, van Dongen JJM . Detection of immunoglobulin kappa light-chain gene rearrangement patterns by Southern blot analysis. Leukemia 1994; 8: 2228–2236.

    CAS  PubMed  Google Scholar 

  25. Tümkaya T, Comans-Bitter WM, Verhoeven MA, van Dongen JJM . Southern blot detection of immunoglobulin lambda light chain gene rearrangements for clonality studies. Leukemia 1995; 9: 2127–2132.

    PubMed  Google Scholar 

  26. Tümkaya T, Beishuizen A, Wolvers-Tettero ILM, van Dongen JJM . Identification of immunoglobulin lambda isotype gene rearrangements by Southern blot analysis. Leukemia 1996; 10: 1834–1839.

    PubMed  Google Scholar 

  27. Moreau EJ, Langerak AW, van Gastel -Mol EJ, Wolvers-Tettero ILM, Zhan M, Zhou Q et al. Easy detection of all T cell receptor gamma (TCRG) gene rearrangements by Southern blot analysis: recommendations for optimal results. Leukemia 1999; 13: 1620–1626.

    Article  CAS  PubMed  Google Scholar 

  28. Langerak AW, Wolvers-Tettero ILM, van Dongen JJM . Detection of T cell receptor beta (TCRB) gene rearrangement patterns in T cell malignancies by Southern blot analysis. Leukemia 1999; 13: 965–974.

    Article  CAS  PubMed  Google Scholar 

  29. Hara J, Benedict SH, Mak TW, Gelfand EW . T cell receptor alpha-chain gene rearrangements in B-precursor leukemia are in contrast to the findings in T cell acute lymphoblastic leukemia. Comparative study of T cell receptor gene rearrangement in childhood leukemia. J Clin Invest 1987; 80: 1770–1777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Szczepanski T, Beishuizen A, Pongers-Willemse MJ, Hählen K, van Wering ER, Wijkhuijs JM et al. Cross-lineage T-cell receptor gene rearrangements occur in more than ninety percent of childhood precursor-B-acute lymphoblastic leukemias: alternative PCR targets for detection of minimal residual disease. Leukemia 1999; 13: 196–205.

    Article  CAS  PubMed  Google Scholar 

  31. Szczepanski T, Langerak AW, van Dongen JJ, van Krieken JH . Lymphoma with multi-gene rearrangement on the level of immunoglobulin heavy chain, light chain, and T-cell receptor beta chain. Am J Hematol 1998; 59: 99–100.

    Article  CAS  PubMed  Google Scholar 

  32. Przybylski G, Oettle H, Ludwig WD, Siegert W, Schmidt CA . Molecular characterization of illegitimate TCR delta gene rearrangements in acute myeloid leukaemia. Br J Haematol 1994; 87: 301–307.

    Article  CAS  PubMed  Google Scholar 

  33. Boeckx N, Willemse MJ, Szczepanski T, van Der Velden VHJ, Langerak AW, Vandekerckhove P et al. Fusion gene transcripts and Ig/TCR gene rearrangements are complementary but infrequent targets for PCR-based detection of minimal residual disease in acute myeloid leukemia. Leukemia 2002; 16: 368–375.

    Article  CAS  PubMed  Google Scholar 

  34. Szczepanski T, Pongers-Willemse MJ, Langerak AW, Harts WA, Wijkhuijs JM, van Wering ER et al. Ig heavy chain gene rearrangements in T-cell acute lymphoblastic leukemia exhibit predominant DH6-19 and DH7-27 gene usage, can result in complete V–D–J rearrangements, and are rare in T-cell receptor αβ lineage. Blood 1999; 93: 4079–4085.

    CAS  PubMed  Google Scholar 

  35. Kluin-Nelemans HC, Kester MG, van deCorput L, Boor PP, Landegent JE, van Dongen JJ et al. Correction of abnormal T-cell receptor repertoire during interferon-alpha therapy in patients with hairy cell leukemia. Blood 1998; 91: 4224–4231.

    CAS  PubMed  Google Scholar 

  36. Sarzotti M, Patel DD, Li X, Ozaki DA, Cao S, Langdon S et al. T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation. J Immunol 2003; 170: 2711–2718.

    Article  CAS  PubMed  Google Scholar 

  37. Mariani S, Coscia M, Even J, Peola S, Foglietta M, Boccadoro M et al. Severe and long-lasting disruption of T-cell receptor diversity in human myeloma after high-dose chemotherapy and autologous peripheral blood progenitor cell infusion. Br J Haematol 2001; 113: 1051–1059.

    Article  CAS  PubMed  Google Scholar 

  38. Davis TH, Yockey CE, Balk SP . Detection of clonal immunoglobulin gene rearrangements by polymerase chain reaction amplification and single-strand conformational polymorphism analysis. Am J Pathol 1993; 142: 1841–1847.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bourguin A, Tung R, Galili N, Sklar J . Rapid, nonradioactive detection of clonal T-cell receptor gene rearrangements in lymphoid neoplasms. Proc Natl Acad Sci USA 1990; 87: 8536–8540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bottaro M, Berti E, Biondi A, Migone N, Crosti L . Heteroduplex analysis of T-cell receptor gamma gene rearrangements for diagnosis and monitoring of cutaneous T-cell lymphomas. Blood 1994; 83: 3271–3278.

    CAS  PubMed  Google Scholar 

  41. Langerak AW, Szczepanski T, van der Burg M, Wolvers-Tettero ILM, van Dongen JJM . Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in suspect T cell proliferations. Leukemia 1997; 11: 2192–2199.

    Article  CAS  PubMed  Google Scholar 

  42. Kneba M, Bolz I, Linke B, Hiddemann W . Analysis of rearranged T-cell receptor beta-chain genes by polymerase chain reaction (PCR) DNA sequencing and automated high resolution PCR fragment analysis. Blood 1995; 86: 3930–3937.

    CAS  PubMed  Google Scholar 

  43. Linke B, Bolz I, Fayyazi A, von Hofen M, Pott C, Bertram J et al. Automated high resolution PCR fragment analysis for identification of clonally rearranged immunoglobulin heavy chain genes. Leukemia 1997; 11: 1055–1062.

    Article  CAS  PubMed  Google Scholar 

  44. Matsuda F, Ishii K, Bourvagnet P, Kuma K, Hayashida H, Miyata T et al. The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J Exp Med 1998; 188: 2151–2162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Camacho FI, Algara P, Rodriguez A, Ruiz-Ballesteros E, Mollejo M, Martinez N et al. Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations. Blood 2003; 101: 4042–4046.

    Article  CAS  PubMed  Google Scholar 

  46. Pritsch O, Troussard X, Magnac C, Mauro FR, Davi F, Payelle-Brogard B et al. VH gene usage by family members affected with chronic lymphocytic leukaemia. Br J Haematol 1999; 107: 616–624.

    Article  CAS  PubMed  Google Scholar 

  47. Rettig MB, Vescio RA, Cao J, Wu CH, Lee JC, Han E et al. VH gene usage is multiple myeloma: complete absence of the VH4.21 (VH4–34) gene. Blood 1996; 87: 2846–2852.

    CAS  PubMed  Google Scholar 

  48. Mortuza FY, Moreira IM, Papaioannou M, Gameiro P, Coyle LA, Gricks CS et al. Immunoglobulin heavy-chain gene rearrangement in adult acute lymphoblastic leukemia reveals preferential usage of J(H)-proximal variable gene segments. Blood 2001; 97: 2716–2726.

    Article  CAS  PubMed  Google Scholar 

  49. Ghia P, ten Boekel E, Rolink AG, Melchers F . B-cell development: a comparison between mouse and man. Immunol Today 1998; 19: 480–485.

    Article  CAS  PubMed  Google Scholar 

  50. Corbett SJ, Tomlinson IM, Sonnhammer ELL, Buck D, Winter G . 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 1997; 270: 587–597.

    Article  CAS  PubMed  Google Scholar 

  51. Ichihara Y, Matsuoka H, Kurosawa Y . Organization of human immunoglobulin heavy chain diversity gene loci. EMBO J 1988; 7: 4141–4150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bertrand III FE, Billips LG, Burrows PD, Gartland GL, Kubagawa H, Schroeder Jr HW . Ig D(H) gene segment transcription and rearrangement before surface expression of the pan-B-cell marker CD19 in normal human bone marrow. Blood 1997; 90: 736–744.

    CAS  PubMed  Google Scholar 

  53. Ghia P, ten Boekel E, Sanz E, de la Hera A, Rolink A, Melchers F . Ordering of human bone marrow B lymphocyte precursors by single-cell polymerase chain reaction analyses of the rearrangement status of the immunoglobulin H and L chain gene loci. J Exp Med 1996; 184: 2217–2229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Szczepanski T, Willemse MJ, van Wering ER, Weerden JF, Kamps WA, van Dongen JJM . Precursor-B-ALL with DH–JH gene rearrangements have an immature immunogenotype with a high frequency of oligoclonality and hyperdiploidy of chromosome 14. Leukemia 2001; 15: 1415–1423.

    Article  CAS  PubMed  Google Scholar 

  55. Davi F, Faili A, Gritti C, Blanc C, Laurent C, Sutton L et al. Early onset of immunoglobulin heavy chain gene rearrangements in normal human bone marrow CD34+ cells. Blood 1997; 90: 4014–4021.

    CAS  PubMed  Google Scholar 

  56. Szczepanski T, van‘t Veer MB, Wolvers-Tettero ILM, Langerak AW, van Dongen JJM . Molecular features responsible for the absence of immunoglobulin heavy chain protein synthesis in an IgH(−) subgroup of multiple myeloma. Blood 2000; 96: 1087–1093.

    CAS  PubMed  Google Scholar 

  57. Schroeder Jr HW, Wang JY . Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc Natl Acad Sci USA 1990; 87: 6146–6150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Raaphorst FM, Raman CS, Tami J, Fischbach M, Sanz I . Human Ig heavy chain CDR3 regions in adult bone marrow pre-B cells display an adult phenotype of diversity: evidence for structural selection of DH amino acid sequences. Int Immunol 1997; 9: 1503–1515.

    Article  CAS  PubMed  Google Scholar 

  59. Lebecque SG, Gearhart PJ . Boundaries of somatic mutation in rearranged immunoglobulin genes: 5′ boundary is near the promoter, and 3′ boundary is approximately 1 kb from V(D)J gene. J Exp Med 1990; 172: 1717–1727.

    Article  CAS  PubMed  Google Scholar 

  60. Fukita Y, Jacobs H, Rajewsky K . Somatic hypermutation in the heavy chain locus correlates with transcription. Immunity 1998; 9: 105–114.

    Article  CAS  PubMed  Google Scholar 

  61. Zachau HG . Immunologist 1996; 4: 49–54.

  62. Lefranc MP . IMGT, the international ImMunoGeneTics database. Nucleic Acids Res 2003; 31: 307–310.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lefranc MP . IMGT databases, web resources and tools for immunoglobulin and T cell receptor sequence analysis, http://imgt.cines.fr. Leukemia 2003; 17: 260–266.

    Article  CAS  PubMed  Google Scholar 

  64. Schäble KF, Zachau HG . The variable genes of the human immunoglobulin kappa locus. Biol Chem Hoppe Seyler 1993; 374: 1001–1022.

    Article  PubMed  Google Scholar 

  65. Weichhold GM, Ohnheiser R, Zachau HG . The human immunoglobulin kappa locus consists of two copies that are organized in opposite polarity. Genomics 1993; 16: 503–511.

    Article  CAS  PubMed  Google Scholar 

  66. Siminovitch KA, Bakhshi A, Goldman P, Korsmeyer SJ . A uniform deleting element mediates the loss of kappa genes in human B cells. Nature 1985; 316: 260–262.

    Article  CAS  PubMed  Google Scholar 

  67. Szczepanski T, Langerak AW, Wolvers-Tettero ILM, Ossenkoppele GJ, Verhoef G, Stul M et al. Immunoglobulin and T cell receptor gene rearrangement patterns in acute lymphoblastic leukemia are less mature in adults than in children: implications for selection of PCR targets for detection of minimal residual disease. Leukemia 1998; 12: 1081–1088.

    Article  CAS  PubMed  Google Scholar 

  68. Van der Velden VHJ, Willemse MJ, van der Schoot CE, van Wering ER, van Dongen JJM . Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targets for detection of minimal residual disease by real-time quantitative PCR. Leukemia 2002; 16: 928–936.

    Article  CAS  PubMed  Google Scholar 

  69. van der Burg M, Tumkaya T, Boerma M, de Bruin-Versteeg S, Langerak AW, van Dongen JJM . Ordered recombination of immunoglobulin light chain genes occurs at the IGK locus but seems less strict at the IGL locus. Blood 2001; 97: 1001–1008.

    Article  CAS  PubMed  Google Scholar 

  70. Cannell PK, Amlot P, Attard M, Hoffbrand AV, Foroni L . Variable kappa gene rearrangement in lymphoproliferative disorders: an analysis of V kappa gene usage, VJ joining and somatic mutation. Leukemia 1994; 8: 1139–1145.

    CAS  PubMed  Google Scholar 

  71. Frippiat JP, Williams SC, Tomlinson IM, Cook GP, Cherif D, Le Paslier D et al. Organization of the human immunoglobulin lambda light-chain locus on chromosome 22q11.2. Hum Mol Genet 1995; 4: 983–991.

    Article  CAS  PubMed  Google Scholar 

  72. Williams SC, Frippiat JP, Tomlinson IM, Ignatovich O, Lefranc MP, Winter G . Sequence and evolution of the human germline V lambda repertoire. J Mol Biol 1996; 264: 220–232.

    Article  CAS  PubMed  Google Scholar 

  73. Kawasaki K, Minoshima S, Nakato E, Shibuya K, Shintani A, Schmeits JL et al. One-megabase sequence analysis of the human immunoglobulin lambda gene locus. Genome Res 1997; 7: 250–261.

    Article  CAS  PubMed  Google Scholar 

  74. Hieter PA, Korsmeyer SJ, Waldmann TA, Leder P . Human immunoglobulin kappa light-chain genes are deleted or rearranged in lambda-producing B cells. Nature 1981; 290: 368–372.

    Article  CAS  PubMed  Google Scholar 

  75. Vasicek TJ, Leder P . Structure and expression of the human immunoglobulin lambda genes. J Exp Med 1990; 172: 609–620.

    Article  CAS  PubMed  Google Scholar 

  76. Taub RA, Hollis GF, Hieter PA, Korsmeyer S, Waldmann TA, Leder P . Variable amplification of immunoglobulin lambda light-chain genes in human populations. Nature 1983; 304: 172–174.

    Article  CAS  PubMed  Google Scholar 

  77. van der Burg M, Barendregt BH, van Gastel-Mol EJ, Tumkaya T, Langerak AW, van Dongen JJ . Unraveling of the polymorphic C lambda 2–C lambda 3 amplification and the Ke+Oz-polymorphism in the human Ig lambda locus. J Immunol 2002; 169: 271–276.

    Article  CAS  PubMed  Google Scholar 

  78. Ignatovich O, Tomlinson IM, Jones PT, Winter G . The creation of diversity in the human immunoglobulin V(lambda) repertoire. J Mol Biol 1997; 268: 69–77.

    Article  CAS  PubMed  Google Scholar 

  79. Bridges Jr SL . Frequent N addition and clonal relatedness among immunoglobulin lambda light chains expressed in rheumatoid arthritis synovia and PBL, and the influence of V lambda gene segment utilization on CDR3 length. Mol Med 1998; 4: 525–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kiyoi H, Naito K, Ohno R, Saito H, Naoe T . Characterization of the immunoglobulin light chain variable region gene expressed in multiple myeloma. Leukemia 1998; 12: 601–609.

    Article  CAS  PubMed  Google Scholar 

  81. Tümkaya T, van der Burg M, Garcia Sanz R, Gonzalez Diaz M, Langerak AW, San Miguel JF et al. Immunoglobulin lambda isotype gene rearrangements in B-cell malignancies. Leukemia 2001; 15: 121–127.

    Article  PubMed  Google Scholar 

  82. Farner NL, Dorner T, Lipsky PE . Molecular mechanisms and selection influence the generation of the human V lambda J lambda repertoire. J Immunol 1999; 162: 2137–2145.

    CAS  PubMed  Google Scholar 

  83. Ignatovich O, Tomlinson IM, Popov AV, Bruggemann M, Winter G . Dominance of intrinsic genetic factors in shaping the human immunoglobulin Vlambda repertoire. J Mol Biol 1999; 294: 457–465.

    Article  CAS  PubMed  Google Scholar 

  84. Arden B, Clark SP, Kabelitz D, Mak TW . Human T-cell receptor variable gene segment families. Immunogenetics 1995; 42: 455–500.

    CAS  PubMed  Google Scholar 

  85. Wei S, Charmley P, Robinson MA, Concannon P . The extent of the human germline T-cell receptor V beta gene segment repertoire. Immunogenetics 1994; 40: 27–36.

    Article  CAS  PubMed  Google Scholar 

  86. Rowen L, Koop BF, Hood L . The complete 685-kilobase DNA sequence of the human beta T cell receptor locus. Science 1996; 272: 1755–1762.

    Article  CAS  PubMed  Google Scholar 

  87. Charmley P, Wei S, Concannon P . Polymorphisms in the TCRB-V2 gene segments localize the Tcrb orphon genes to human chromosome 9p21. Immunogenetics 1993; 38: 283–286.

    CAS  PubMed  Google Scholar 

  88. Robinson MA, Mitchell MP, Wei S, Day CE, Zhao TM, Concannon P . Organization of human T-cell receptor beta-chain genes: clusters of V beta genes are present on chromosomes 7 and 9. Proc Natl Acad Sci USA 1993; 90: 2433–2437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Toyonaga B, Yoshikai Y, Vadasz V, Chin B, Mak TW . Organization and sequences of the diversity, joining, and constant region genes of the human T-cell receptor beta chain. Proc Natl Acad Sci USA 1985; 82: 8624–8628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu D, Callahan JP, Dau PC . Intrafamily fragment analysis of the T cell receptor beta chain CDR3 region. J Immunol Methods 1995; 187: 139–150.

    Article  CAS  PubMed  Google Scholar 

  91. Tsuda S, Rieke S, Hashimoto Y, Nakauchi H, Takahama Y . Il-7 supports D–J but not V–DJ rearrangement of TCR-beta gene in fetal liver progenitor cells. J Immunol 1996; 156: 3233–3242.

    CAS  PubMed  Google Scholar 

  92. Weidmann E, Whiteside TL, Giorda R, Herberman RB, Trucco M . The T-cell receptor V beta gene usage in tumor-infiltrating lymphocytes and blood of patients with hepatocellular carcinoma. Cancer Res 1992; 52: 5913–5920.

    CAS  PubMed  Google Scholar 

  93. Jores R, Meo T . Few V gene segments dominate the T cell receptor beta-chain repertoire of the human thymus. J Immunol 1993; 151: 6110–6122.

    CAS  PubMed  Google Scholar 

  94. Rosenberg WM, Moss PA, Bell JI . Variation in human T cell receptor V beta and J beta repertoire: analysis using anchor polymerase chain reaction. Eur J Immunol 1992; 22: 541–549.

    Article  CAS  PubMed  Google Scholar 

  95. Pongers-Willemse MJ, Seriu T, Stolz F, d’Aniello E, Gameiro P, Pisa P et al. Primers and protocols for standardized MRD detection in ALL using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13: 110–118.

    Article  CAS  PubMed  Google Scholar 

  96. Hansen-Hagge TE, Yokota S, Bartram CR . Detection of minimal residual disease in acute lymphoblastic leukemia by in vitro amplification of rearranged T-cell receptor delta chain sequences. Blood 1989; 74: 1762–1767.

    CAS  PubMed  Google Scholar 

  97. Cave H, Guidal C, Rohrlich P, Delfau MH, Broyart A, Lescoeur B et al. Prospective monitoring and quantitation of residual blasts in childhood acute lymphoblastic leukemia by polymerase chain reaction study of delta and gamma T-cell receptor genes. Blood 1994; 83: 1892–1902.

    CAS  PubMed  Google Scholar 

  98. Gorski J, Yassai M, Zhu X, Kissela B, Kissella B, Keever C et al. Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status. J Immunol 1994; 152: 5109–5119.

    CAS  PubMed  Google Scholar 

  99. McCarthy KP, Sloane JP, Kabarowski JH, Matutes E, Wiedemann LM . The rapid detection of clonal T-cell proliferations in patients with lymphoid disorders. Am J Pathol 1991; 138: 821–828.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Assaf C, Hummel M, Dippel E, Goerdt S, Muller HH, Anagnostopoulos I et al. High detection rate of T-cell receptor beta chain rearrangements in T-cell lymphoproliferations by family specific polymerase chain reaction in combination with the GeneScan technique and DNA sequencing. Blood 2000; 96: 640–646.

    CAS  PubMed  Google Scholar 

  101. O'Shea U, Wyatt JI, Howdle PD . Analysis of T cell receptor beta chain CDR3 size using RNA extracted from formalin fixed paraffin wax embedded tissue. J Clin Pathol 1997; 50: 811–814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Duby AD, Seidman JG . Abnormal recombination products result from aberrant DNA rearrangement of the human T-cell antigen receptor beta-chain gene. Proc Natl Acad Sci USA 1986; 83: 4890–4894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Alatrakchi N, Farace F, Frau E, Carde P, Munck JN, Triebel F . T-cell clonal expansion in patients with B-cell lymphoproliferative disorders. J Immunother 1998; 21: 363–370.

    Article  CAS  PubMed  Google Scholar 

  104. Blom B, Verschuren MC, Heemskerk MH, Bakker AQ, van Gastel-Mol EJ, Wolvers-Tettero IL et al. TCR gene rearrangements and expression of the pre-T cell receptor complex during human T-cell differentiation. Blood 1999; 93: 3033–3043.

    CAS  PubMed  Google Scholar 

  105. Chen Z, Font MP, Loiseau P, Bories JC, Degos L, Lefranc MP et al. The human T-cell V gamma gene locus: cloning of new segments and study of V gamma rearrangements in neoplastic T and B cells. Blood 1988; 72: 776–783.

    CAS  PubMed  Google Scholar 

  106. Zhang XM, Tonnelle C, Lefranc MP, Huck S . T cell receptor gamma cDNA in human fetal liver and thymus: variable regions of gamma chains are restricted to V gamma I or V9, due to the absence of splicing of the V10 and V11 leader intron. Eur J Immunol 1994; 24: 571–578.

    Article  CAS  PubMed  Google Scholar 

  107. Huck S, Lefranc MP . Rearrangements to the JP1, JP and JP2 segments in the human T-cell rearranging gamma gene (TRG gamma) locus. FEBS Lett 1987; 224: 291–296.

    Article  CAS  PubMed  Google Scholar 

  108. Quertermous T, Strauss WM, van Dongen JJ, Seidman JG . Human T cell gamma chain joining regions and T cell development. J Immunol 1987; 138: 2687–2690.

    CAS  PubMed  Google Scholar 

  109. Delfau MH, Hance AJ, Lecossier D, Vilmer E, Grandchamp B . Restricted diversity of V gamma 9-JP rearrangements in unstimulated human gamma/delta T lymphocytes. Eur J Immunol 1992; 22: 2437–2443.

    Article  CAS  PubMed  Google Scholar 

  110. Porcelli S, Brenner MB, Band H . Biology of the human gamma delta T-cell receptor. Immunol Rev 1991; 120: 137–183.

    Article  CAS  PubMed  Google Scholar 

  111. Szczepanski T, Langerak AW, Willemse MJ, Wolvers-Tettero ILM, van Wering ER, van Dongen JJM . T cell receptor gamma (TCRG) gene rearrangements in T cell acute lymphoblastic leukemia reflect ‘end-stage’ recombinations: implications for minimal residual disease monitoring. Leukemia 2000; 14: 1208–1214.

    Article  CAS  PubMed  Google Scholar 

  112. Delabesse E, Burtin ML, Millien C, Madonik A, Arnulf B, Beldjord K et al. Rapid, multifluorescent TCRG Vgamma and Jgamma typing: application to T cell acute lymphoblastic leukemia and to the detection of minor clonal populations. Leukemia 2000; 14: 1143–1152.

    Article  CAS  PubMed  Google Scholar 

  113. Van der Velden VHJ, Wijkhuijs JM, Jacobs DCH, van Wering ER, van Dongen JJM . T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis. Leukemia 2002; 16: 1372–1380.

    Article  CAS  PubMed  Google Scholar 

  114. Taylor JJ, Rowe D, Reid MM, Middleton PG . An interstitial deletion in the rearranged T-cell receptor gamma chain locus in a case of T-cell acute lymphoblastic leukaemia. Br J Haematol 1993; 85: 193–196.

    Article  CAS  PubMed  Google Scholar 

  115. Castellanos A, Martin-Seisdedos C, Toribio ML, San Miguel JF, Gonzalez Sarmiento R . TCR-gamma gene rearrangement with interstitial deletion within the TRGV2 gene segment is not detected in normal T-lymphocytes. Leukemia 1998; 12: 251–253.

    Article  CAS  PubMed  Google Scholar 

  116. Verschuren MC, Wolvers-Tettero IL, Breit TM, van Dongen JJ . T-cell receptor V delta–J alpha rearrangements in human thymocytes: the role of V delta–J alpha rearrangements in T-cell receptor-delta gene deletion. Immunology 1998; 93: 208–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. WHO-IUIS Nomenclature Sub-Committee on TCR Designation. Nomenclature for T-cell receptor (TCR) gene segments of the immune system. Immunogenetics 1995; 42: 451–453.

  118. Kabelitz D, Wesch D, Hinz T . Gamma delta T cells, their T cell receptor usage and role in human diseases. Springer Semin Immunopathol 1999; 21: 55–75.

    CAS  PubMed  Google Scholar 

  119. Shen J, Andrews DM, Pandolfi F, Boyle LA, Kersten CM, Blatman RN et al. Oligoclonality of Vdelta1 and Vdelta2 cells in human peripheral blood mononuclear cells: TCR selection is not altered by stimulation with Gram-negative bacteria. J Immunol 1998; 160: 3048–3055.

    CAS  PubMed  Google Scholar 

  120. Alaibac M, Daga A, Harms G, Morris J, Yu RC, Zwingerberger K et al. Molecular analysis of the gamma delta T-cell receptor repertoire in normal human skin and in Oriental cutaneous leishmaniasis. Exp Dermatol 1993; 2: 106–112.

    Article  CAS  PubMed  Google Scholar 

  121. Nordlind K, Liden S . Gamma/delta T cells and human skin reactivity to heavy metals. Arch Dermatol Res 1995; 287: 137–141.

    Article  CAS  PubMed  Google Scholar 

  122. Deusch K, Pfeffer K, Reich K, Gstettenbauer M, Daum S, Luling F et al. Phenotypic and functional characterization of human TCR gamma delta+ intestinal intraepithelial lymphocytes. Curr Top Microbiol Immunol 1991; 173: 279–283.

    CAS  PubMed  Google Scholar 

  123. Trejdosiewicz LK, Calabrese A, Smart CJ, Oakes DJ, Howdle PD, Crabtree JE et al. Gamma delta T cell receptor-positive cells of the human gastrointestinal mucosa: occurrence and V region gene expression in Heliobacter pylori-associated gastritis, coeliac disease and inflammatory bowel disease. Clin Exp Immunol 1991; 84: 440–444.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Breit TM, Wolvers-Tettero ILM, Hählen K, Van Wering ER, van Dongen JJM . Extensive junctional diversity of γδ T-cell receptors expressed by T-cell acute lymphoblastic leukemias: implications for the detection of minimal residual disease. Leukemia 1991; 5: 1076–1086.

    CAS  PubMed  Google Scholar 

  125. Langlands K, Eden OB, Micallef-Eynaud P, Parker AC, Anthony RS . Direct sequence analysis of TCR V delta 2–D delta 3 rearrangements in common acute lymphoblastic leukaemia and application to detection of minimal residual disease. Br J Haematol 1993; 84: 648–655.

    Article  CAS  PubMed  Google Scholar 

  126. Schneider M, Panzer S, Stolz F, Fischer S, Gadner H, Panzer-Grumayer ER . Crosslineage TCR delta rearrangements occur shortly after the DJ joinings of the IgH genes in childhood precursor B ALL and display age-specific characteristics. Br J Haematol 1997; 99: 115–121.

    Article  CAS  PubMed  Google Scholar 

  127. Hettinger K, Fischer S, Panzer S, Panzer-Grumayer ER . Multiplex PCR for TCR delta rearrangements: a rapid and specific approach for the detection and identification of immature and mature rearrangements in ALL. Br J Haematol 1998; 102: 1050–1054.

    Article  CAS  PubMed  Google Scholar 

  128. Theodorou I, Raphael M, Bigorgne C, Fourcade C, Lahet C, Cochet G et al. Recombination pattern of the TCR gamma locus in human peripheral T-cell lymphomas. J Pathol 1994; 174: 233–242.

    Article  CAS  PubMed  Google Scholar 

  129. Kanavaros P, Farcet JP, Gaulard P, Haioun C, Divine M, Le Couedic JP et al. Recombinative events of the T cell antigen receptor delta gene in peripheral T cell lymphomas. J Clin Invest 1991; 87: 666–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Przybylski GK, Wu H, Macon WR, Finan J, Leonard DG, Felgar RE et al. Hepatosplenic and subcutaneous panniculitis-like gamma/delta T cell lymphomas are derived from different Vdelta subsets of gamma/delta T lymphocytes. J Mol Diagn 2000; 2: 11–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kadin ME . Cutaneous gamma delta T-cell lymphomas – how and why should they be recognized? Arch Dermatol 2000; 136: 1052–1054.

    Article  CAS  PubMed  Google Scholar 

  132. Hodges E, Quin C, Farrell AM, Christmas S, Sewell HF, Doherty M et al. Arthropathy, leucopenia and recurrent infection associated with a TcR gamma delta population. Br J Rheumatol 1995; 34: 978–983.

    Article  CAS  PubMed  Google Scholar 

  133. Van Oostveen JW, Breit TM, de Wolf JT, Brandt RM, Smit JW, van Dongen JJM et al. Polyclonal expansion of T-cell receptor–γδ+ T lymphocytes associated with neutropenia and thrombocytopenia. Leukemia 1992; 6: 410–418.

    CAS  PubMed  Google Scholar 

  134. Borst J, Wicherink A, van Dongen JJ, De Vries E, Comans-Bitter WM, Wassenaar F et al. Non-random expression of T cell receptor gamma and delta variable gene segments in functional T lymphocyte clones from human peripheral blood. Eur J Immunol 1989; 19: 1559–1568.

    Article  CAS  PubMed  Google Scholar 

  135. Krejci O, Prouzova Z, Horvath O, Trka J, Hrusak O . TCR delta gene is frequently rearranged in adult B lymphocytes. J Immunol 2003; 171: 524–527.

    Article  CAS  PubMed  Google Scholar 

  136. Triebel F, Faure F, Mami-Chouaib F, Jitsukawa S, Griscelli A, Genevee C et al. A novel human V delta gene expressed predominantly in the Ti gamma A fraction of gamma/delta+ peripheral lymphocytes. Eur J Immunol 1988; 18: 2021–2027.

    Article  CAS  PubMed  Google Scholar 

  137. De Boer CJ, van Krieken JH, Schuuring E, Kluin PM . Bcl-1/cyclin D1 in malignant lymphoma. Ann Oncol 1997; 8: 109–117.

    Article  PubMed  Google Scholar 

  138. Tsujimoto Y, Yunis J, Onorato-Showe L, Erikson J, Nowell PC, Croce CM . Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 1984; 224: 1403–1406.

    Article  CAS  PubMed  Google Scholar 

  139. Vaandrager JW, Kleiverda JK, Schuuring E, Kluin-Nelemans JC, Raap AK, Kluin PM . Cytogenetics on released DNA fibers. Verh Dtsch Ges Pathol 1997; 81: 306–311.

    CAS  PubMed  Google Scholar 

  140. Vaandrager JW, Schuuring E, Zwikstra E, de Boer CJ, Kleiverda KK, van Krieken JH et al. Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell lymphoma by multicolor DNA fiber fluorescence in situ hybridization. Blood 1996; 88: 1177–1182.

    CAS  PubMed  Google Scholar 

  141. Pott C, Tiemann M, Linke B, Ott MM, von Hofen M, Bolz I et al. Structure of Bcl-1 and IgH-CDR3 rearrangements as clonal markers in mantle cell lymphomas. Leukemia 1998; 12: 1630–1637.

    Article  CAS  PubMed  Google Scholar 

  142. Luthra R, Hai S, Pugh WC . Polymerase chain reaction detection of the t(11;14) translocation involving the bcl-1 major translocation cluster in mantle cell lymphoma. Diagn Mol Pathol 1995; 4: 4–7.

    Article  CAS  PubMed  Google Scholar 

  143. de Boer CJ, Schuuring E, Dreef E, Peters G, Bartek J, Kluin PM et al. Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma. Blood 1995; 86: 2715–2723.

    CAS  PubMed  Google Scholar 

  144. Haralambieva E, Kleiverda K, Mason DY, Schuuring E, Kluin PM . Detection of three common translocation breakpoints in non-Hodgkin's lymphomas by fluorescence in situ hybridization on routine paraffin-embedded tissue sections. J Pathol 2002; 198: 163–170.

    Article  CAS  PubMed  Google Scholar 

  145. Williams ME, Swerdlow SH, Meeker TC . Chromosome t(11;14)(q13;q32) breakpoints in centrocytic lymphoma are highly localized at the bcl-1 major translocation cluster. Leukemia 1993; 7: 1437–1440.

    CAS  PubMed  Google Scholar 

  146. Segal GH, Masih AS, Fox AC, Jorgensen T, Scott M, Braylan RC . CD5-expressing B-cell non-Hodgkin's lymphomas with bcl-1 gene rearrangement have a relatively homogeneous immunophenotype and are associated with an overall poor prognosis. Blood 1995; 85: 1570–1579.

    CAS  PubMed  Google Scholar 

  147. Janssen JW, Vaandrager JW, Heuser T, Jauch A, Kluin PM, Geelen E et al. Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32). Blood 2000; 95: 2691–2698.

    CAS  PubMed  Google Scholar 

  148. Troussard X, Mauvieux L, Radford-Weiss I, Rack K, Valensi F, Garand R et al. Genetic analysis of splenic lymphoma with villous lymphocytes: a Groupe Francais d’Hematologie Cellulaire (GFHC) study. Br J Haematol 1998; 101: 712–721.

    Article  CAS  PubMed  Google Scholar 

  149. Limpens J, Stad R, Vos C, de Vlaam C, de Jong D, van Ommen GJ et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 1995; 85: 2528–2536.

    CAS  PubMed  Google Scholar 

  150. Rabbitts P, Douglas J, Fischer P, Nacheva E, Karpas A, Catovsky D et al. Chromosome abnormalities at 11q13 in B cell tumours. Oncogene 1988; 3: 99–103.

    CAS  Google Scholar 

  151. Fukuhara S, Rowley JD, Variakojis D, Golomb HM . Chromosome abnormalities in poorly differentiated lymphocytic lymphoma. Cancer Res 1979; 39: 3119–3128.

    CAS  PubMed  Google Scholar 

  152. Weiss LM, Warnke RA, Sklar J, Cleary ML . Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 1987; 317: 1185–1189.

    Article  CAS  PubMed  Google Scholar 

  153. Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41: 899–906.

    Article  CAS  PubMed  Google Scholar 

  154. Cleary ML, Sklar J . Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA 1985; 82: 7439–7443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Korsmeyer SJ . BCL-2 gene family and the regulation of programmed cell death. Cancer Res 1999; 59: 1693s–1700s.

    CAS  PubMed  Google Scholar 

  156. Lithgow T, van Driel R, Bertram JF, Strasser A . The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth Differ 1994; 5: 411–417.

    CAS  PubMed  Google Scholar 

  157. Woodland RT, Schmidt MR, Korsmeyer SJ, Gravel KA . Regulation of B cell survival in xid mice by the proto-oncogene bcl-2. J Immunol 1996; 156: 2143–2154.

    CAS  PubMed  Google Scholar 

  158. Hsu SY, Lai RJ, Finegold M, Hsueh AJ . Targeted overexpression of Bcl-2 in ovaries of transgenic mice leads to decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis. Endocrinology 1996; 137: 4837–4843.

    Article  CAS  PubMed  Google Scholar 

  159. Lee MS, Chang KS, Cabanillas F, Freireich EJ, Trujillo JM, Stass SA . Detection of minimal residual cells carrying the t(14;18) by DNA sequence amplification. Science 1987; 237: 175–178.

    Article  CAS  PubMed  Google Scholar 

  160. Crescenzi M, Seto M, Herzig GP, Weiss PD, Griffith RC, Korsmeyer SJ . Thermostable DNA polymerase chain amplification of t(14;18) chromosome breakpoints and detection of minimal residual disease. Proc Natl Acad Sci USA 1988; 85: 4869–4873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lee MS . Molecular aspects of chromosomal translocation t(14;18). Semin Hematol 1993; 30: 297–305.

    CAS  PubMed  Google Scholar 

  162. Buchonnet G, Lenain P, Ruminy P, Lepretre S, Stamatoullas A, Parmentier F et al. Characterisation of BCL2-JH rearrangements in follicular lymphoma: PCR detection of 3′ BCL2 breakpoints and evidence of a new cluster. Leukemia 2000; 14: 1563–1569.

    Article  CAS  PubMed  Google Scholar 

  163. Cleary ML, Galili N, Sklar J . Detection of a second t(14;18) breakpoint cluster region in human follicular lymphomas. J Exp Med 1986; 164: 315–320.

    Article  CAS  PubMed  Google Scholar 

  164. Akasaka T, Akasaka H, Yonetani N, Ohno H, Yamabe H, Fukuhara S et al. Refinement of the BCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets. Genes Chromosomes Cancer 1998; 21: 17–29.

    Article  CAS  PubMed  Google Scholar 

  165. 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.

    CAS  PubMed  Google Scholar 

  166. Yabumoto K, Akasaka T, Muramatsu M, Kadowaki N, Hayashi T, Ohno H et al. Rearrangement of the 5′ cluster region of the BCL2 gene in lymphoid neoplasm: a summary of nine cases. Leukemia 1996; 10: 970–977.

    CAS  PubMed  Google Scholar 

  167. Pezzella F, Ralfkiaer E, Gatter KC, Mason DY . The 14;18 translocation in European cases of follicular lymphoma: comparison of Southern blotting and the polymerase chain reaction. Br J Haematol 1990; 76: 58–64.

    Article  CAS  PubMed  Google Scholar 

  168. Turner GE, Ross FM, Krajewski AS . Detection of t(14;18) in British follicular lymphoma using cytogenetics, Southern blotting and the polymerase chain reaction. Br J Haematol 1995; 89: 223–225.

    Article  CAS  PubMed  Google Scholar 

  169. Vaandrager JW, Schuuring E, Raap T, Philippo K, Kleiverda K, Kluin P . Interphase FISH detection of BCL2 rearrangement in follicular lymphoma using breakpoint-flanking probes. Genes Chromosomes Cancer 2000; 27: 85–94.

    Article  CAS  PubMed  Google Scholar 

  170. Vaandrager JW, Schuuring E, Kluin-Nelemans HC, Dyer MJ, Raap AK, Kluin PM . DNA fiber fluorescence in situ hybridization analysis of immunoglobulin class switching in B-cell neoplasia: aberrant CH gene rearrangements in follicle center-cell lymphoma. Blood 1998; 92: 2871–2878.

    CAS  PubMed  Google Scholar 

  171. Jacobson JO, Wilkes BM, Kwaiatkowski DJ, Medeiros LJ, Aisenberg AC, Harris NL . bcl-2 rearrangements in de novo diffuse large cell lymphoma. Association with distinctive clinical features. Cancer 1993; 72: 231–236.

    Article  CAS  PubMed  Google Scholar 

  172. Hill ME, MacLennan KA, Cunningham DC, Vaughan Hudson B, Burke M, Clarke P et al. Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study. Blood 1996; 88: 1046–1051.

    CAS  PubMed  Google Scholar 

  173. Vaandrager JW, Schuuring E, Philippo K, Kluin PM . V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma. Blood 2000; 96: 1947–1952.

    CAS  PubMed  Google Scholar 

  174. Fenton JA, Vaandrager JW, Aarts WM, Bende RJ, Heering K, van Dijk M et al. Follicular lymphoma with a novel t(14;18) breakpoint involving the immunoglobulin heavy chain switch mu region indicates an origin from germinal center B cells. Blood 2002; 99: 716–718.

    Article  CAS  PubMed  Google Scholar 

  175. Alaibac M, Filotico R, Giannella C, Paradiso A, Labriola A, Marzullo F . The effect of fixation type on DNA extracted from paraffin-embedded tissue for PCR studies in dermatopathology. Dermatology 1997; 195: 105–107.

    Article  CAS  PubMed  Google Scholar 

  176. An SF, Fleming KA . Removal of inhibitor(s) of the polymerase chain reaction from formalin fixed, paraffin wax embedded tissues. J Clin Pathol 1991; 44: 924–927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Camilleri-Broet S, Devez F, Tissier F, Ducruit V, Le Tourneau A, Diebold J et al. Quality control and sensitivity of polymerase chain reaction techniques for the assessment of immunoglobulin heavy chain gene rearrangements from fixed- and paraffin-embedded samples. Ann Diagn Pathol 2000; 4: 71–76.

    Article  CAS  PubMed  Google Scholar 

  178. Greer CE, Peterson SL, Kiviat NB, Manos MM . PCR amplification from paraffin-embedded tissues. Effects of fixative and fixation time. Am J Clin Pathol 1991; 95: 117–124.

    Article  CAS  PubMed  Google Scholar 

  179. Legrand B, Mazancourt P, Durigon M, Khalifat V, Crainic K . DNA genotyping of unbuffered formalin fixed paraffin embedded tissues. Forensic Sci Int 2002; 125: 205–211.

    Article  CAS  PubMed  Google Scholar 

  180. Lo YM, Mehal WZ, Fleming KA . In vitro amplification of hepatitis B virus sequences from liver tumour DNA and from paraffin wax embedded tissues using the polymerase chain reaction. J Clin Pathol 1989; 42: 840–846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Longy M, Duboue B, Soubeyran P, Moynet D . Method for the purification of tissue DNA suitable for PCR after fixation with Bouin's fluid. Uses and limitations in microsatellite typing. Diagn Mol Pathol 1997; 6: 167–173.

    Article  CAS  PubMed  Google Scholar 

  182. Sato Y, Sugie R, Tsuchiya B, Kameya T, Natori M, Mukai K . Comparison of the DNA extraction methods for polymerase chain reaction amplification from formalin-fixed and paraffin-embedded tissues. Diagn Mol Pathol 2001; 10: 265–271.

    Article  CAS  PubMed  Google Scholar 

  183. Tbakhi A, Totos G, Pettay JD, Myles J, Tubbs RR . The effect of fixation on detection of B-cell clonality by polymerase chain reaction. Mod Pathol 1999; 12: 272–278.

    CAS  PubMed  Google Scholar 

  184. Goelz SE, Hamilton SR, Vogelstein B . Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem Biophys Res Commun 1985; 130: 118–126.

    Article  CAS  PubMed  Google Scholar 

  185. Chan PK, Chan DP, To KF, Yu MY, Cheung JL, Cheng AF . Evaluation of extraction methods from paraffin wax embedded tissues for PCR amplification of human and viral DNA. J Clin Pathol 2001; 54: 401–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Coombs NJ, Gough AC, Primrose JN . Optimisation of DNA and RNA extraction from archival formalin-fixed tissue. Nucleic Acids Res 1999; 27: e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Wickham CL, Boyce M, Joyner MV, Sarsfield P, Wilkins BS, Jones DB et al. Amplification of PCR products in excess of 600 base pairs using DNA extracted from decalcified, paraffin wax embedded bone marrow trephine biopsies. Mol Pathol 2000; 53: 19–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Cawkwell L, Quirke P . Direct multiplex amplification of DNA from a formalin fixed, paraffin wax embedded tissue section. Mol Pathol 2000; 53: 51–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Diaz-Cano SJ, Brady SP . DNA extraction from formalin-fixed, paraffin-embedded tissues: protein digestion as a limiting step for retrieval of high-quality DNA. Diagn Mol Pathol 1997; 6: 342–346.

    Article  CAS  PubMed  Google Scholar 

  190. Hoeve MA, Krol AD, Philippo K, Derksen PW, Veenendaal RA, Schuuring E et al. Limitations of clonality analysis of B cell proliferations using CDR3 polymerase chain reaction. Mol Pathol 2000; 53: 194–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Zhou XG, Sandvej K, Gregersen N, Hamilton-Dutoit SJ . Detection of clonal B cells in microdissected reactive lymphoproliferations: possible diagnostic pitfalls in PCR analysis of immunoglobulin heavy chain gene rearrangement. Mol Pathol 1999; 52: 104–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Drexler HG . The Leukemia-Lymphoma Cell Line Facts Book, Factsbook Series London: Academic Press, 2001.

    Google Scholar 

  193. Drexler HG, Dirks WG, Matsuo Y, MacLeod RA . False leukemia-lymphoma cell lines: an update on over 500 cell lines. Leukemia 2003; 17: 416–426.

    Article  CAS  PubMed  Google Scholar 

  194. Beishuizen A, de Bruijn MA, Pongers-Willemse MJ, Verhoeven MA, van Wering ER, Hahlen K et al. Heterogeneity in junctional regions of immunoglobulin kappa deleting element rearrangements in B cell leukemias: a new molecular target for detection of minimal residual disease. Leukemia 1997; 11: 2200–2207.

    Article  CAS  PubMed  Google Scholar 

  195. Szczepanski T, Flohr T, van der Velden VH, Bartram CR, van Dongen JJ . Molecular monitoring of residual disease using antigen receptor genes in childhood acute lymphoblastic leukaemia. Best Pract Res Clin Haematol 2002; 15: 37–57.

    Article  CAS  PubMed  Google Scholar 

  196. Willemse MJ, Seriu T, Hettinger K, d’Aniello E, Hop WC, Panzer-Grumayer ER et al. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 2002; 99: 4386–4393.

    Article  CAS  PubMed  Google Scholar 

  197. Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer – Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339: 591–598.

    Article  CAS  PubMed  Google Scholar 

  198. van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731–1738.

    Article  CAS  PubMed  Google Scholar 

  199. zur Stadt U, Harms DO, Schluter S, Schrappe M, Goebel U, Spaar H et al. MRD at the end of induction therapy in childhood acute lymphoblastic leukemia: outcome prediction strongly depends on the therapeutic regimen. Leukemia 2001; 15: 283–285.

    Article  CAS  PubMed  Google Scholar 

  200. Schmiegelow K, Nyvold C, Seyfarth J, Pieters R, Rottier MM, Knabe N et al. Post-induction residual leukemia in childhood acute lymphoblastic leukemia quantified by PCR correlates with in vitro prednisolone resistance. Leukemia 2001; 15: 1066–1071.

    Article  CAS  PubMed  Google Scholar 

  201. Knechtli CJ, Goulden NJ, Hancock JP, Grandage VL, Harris EL, Garland RJ et al. Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood 1998; 92: 4072–4079.

    CAS  PubMed  Google Scholar 

  202. van der Velden VH, Joosten SA, Willemse MJ, van Wering ER, Lankester AW, van Dongen JJ et al. Real-time quantitative PCR for detection of minimal residual disease before allogeneic stem cell transplantation predicts outcome in children with acute lymphoblastic leukemia. Leukemia 2001; 15: 1485–1487.

    Article  CAS  PubMed  Google Scholar 

  203. Bader P, Hancock J, Kreyenberg H, Goulden NJ, Niethammer D, Oakhill A et al. Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. Leukemia 2002; 16: 1668–1672.

    Article  CAS  PubMed  Google Scholar 

  204. Guidal C, Vilmer E, Grandchamp B, Cave H . A competitive PCR-based method using TCRD, TCRG and IGH rearrangements for rapid detection of patients with high levels of minimal residual disease in acute lymphoblastic leukemia. Leukemia 2002; 16: 762–764.

    Article  CAS  PubMed  Google Scholar 

  205. Wagner SD, Luzzatto L . V kappa gene segments rearranged in chronic lymphocytic leukemia are distributed over a large portion of the V kappa locus and do not show somatic mutation. Eur J Immunol 1993; 23: 391–397.

    Article  CAS  PubMed  Google Scholar 

  206. Wagner SD, Martinelli V, Luzzatto L . Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma. Blood 1994; 83: 3647–3653.

    CAS  PubMed  Google Scholar 

  207. Solomon A . Light chains of immunoglobulins: structural–genetic correlates. Blood 1986; 68: 603–610.

    CAS  PubMed  Google Scholar 

  208. Cuisinier AM, Fumoux F, Moinier D, Boubli L, Guigou V, Milili M et al. Rapid expansion of human immunoglobulin repertoire (VH, V kappa, V lambda) expressed in early fetal bone marrow. New Biol 1990; 2: 689–699.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the teams of the National Network Leaders and the technicians of the participating laboratories for their continuous support to make this European collaboration successful. We gratefully acknowledge Professor Martin Dyer, University of Leicester, for the kind gift of cell lines K231, Oz, and SC1.We thank Marieke Comans-Bitter for the design of the high-quality figures, which turned out to be essential for summarizing the Concerted Action results. We are grateful to Gellof van Steenis and Winnie Monster-Hoogendoorn for their support in the completion of the financial administration of the EU project. Finally, we thank the secretaries of the coordinating center in Rotterdam for their continuous support, particularly Danielle Korpershoek, Annella Boon and Bibi van Bodegom.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J J M van Dongen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Dongen, J., Langerak, A., Brüggemann, M. 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 17, 2257–2317 (2003). https://doi.org/10.1038/sj.leu.2403202

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403202

Keywords

This article is cited by

Search

Quick links