Genetic Rearrangements of Human Immunoglobulin Genes

  • Stanley J. Korsmeyer
  • Ajay Bakhshi
  • Andrew Arnold
  • Katherine A. Siminovitch
  • Thomas A. Waldmann


The immunoglobulin (Ig) genes ultimately responsible for the generation of antibody diversity and thus the uniqueness or idiotype of each individual molecule produced are organized in a subsegmental, discontinuous fashion in their germ-line form.(1–4) As we will explore, the design of these coding gene subsegments and even the probable mechanisms for their DNA assemblage have been remarkably conserved over evolutionary time.(5–9) This elaborate system utilizes movable gene subsegments, flexibility at the sites of their recombination, and somatic mutation to maximize the number of unique antibody molecules that can be generated from a necessarily limited amount of germline material. While the somatic process of gene recombination creates an amazing diversity of products, these rearrangements have also proven to be rather error-prone. Multiple, alternative chances and choices for assembling an Ig gene appear to compensate for these abortive attempts. We will show that the assemblage of Ig gene subsegments occurs in a sequential fashion during early B-cell development and helps ensure that the final B cell makes but a single Ig molecule. This hierarchy of Ig gene recombination events, mandatory during B-cell development, has proved of great importance in assessing the clonality and stage of differentiation of a variety of human neoplasms. Following the rearrangements that generate the antibody diversity and idiotypes necessary for immune regulation, the Ig gene loci may at times undergo an additional recombination. As we will see, this latter rearrangement is one between chromosomes and results in the translocation of a cellular oncogene to an Ig gene locus within certain human B-cell malignancies.


Gene Rearrangement Germline Gene Genetic Rearrangement Antibody Diversity Cellular Oncogene 
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  1. 1.
    Dreyer, W. J., and Bennett, J. C., 1965, The molecular basis of antibody formation: A paradox, Proc. Natl. Acad. Sci. USA 54:864–869.PubMedCrossRefGoogle Scholar
  2. 2.
    Hozumi, N., and Tonegawa, S., 1976, Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions, Proc. Natl. Acad. Sci. USA 73:3628–3632.PubMedCrossRefGoogle Scholar
  3. 3.
    Brack, C., Hirama, M., Lenhard-Schuller, R., and Tonegawa, S., 1978, A complete imunoglobulin gene is created by somatic recombination, Cell 15:1–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Seidman, J. G., and Leder, P., 1978, The arrangement and rearrangement of antibody genes,Nature 276:790–795.PubMedCrossRefGoogle Scholar
  5. 5.
    Hieter, P. A., Max, E. E., Seidman, J. G., Maizel, J. V., Jr., and Leder, P., 1980, Cloned human and mouse kappa immunoglobulin constant and J region genes conserve homology in functional segments, Cell 22:197–207.PubMedCrossRefGoogle Scholar
  6. 6.
    Hieter, P. A., Maizel, J. V., Jr., and Leder, P., 1982, Evolution of human immunoglobulin K J region genes,j. Biol. Chem. 257:1516–1522.PubMedGoogle Scholar
  7. 7.
    Hieter, P. A., Hollis, G. F., Korsmeyer, S. J., Waldmann, T. A., and Leder, P., 1981, Clustered arrangement of immunoglobulin X constant region genes in man, Nature 294:536–540.PubMedCrossRefGoogle Scholar
  8. 8.
    Ravetch, J. V., Siebenlist, U., Korsmeyer, S., Waldmann, T., and Leder, P., 1981, Structure of the human immunoglobulin µ locus: Characterization of embryonic and rearranged J and D genes, Cell 27:583–591.PubMedCrossRefGoogle Scholar
  9. 9.
    Siebenlist, U., Ravetch, J. V., Korsmeyer, S. J., Waldmann, T. A., and Leder, P., 1981, Human immunoglobulin D segments encoded in tandem multigenic families, Nature 294:631–635.PubMedCrossRefGoogle Scholar
  10. 10.
    Early, P., Huang, H., Davis, M., Calame, K., and Hood, L., 1980, An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH, Cell 19:981–992.PubMedCrossRefGoogle Scholar
  11. 11.
    Sakano, H., Kurosawa, Y., Weigert, M., and Tonegawa, S., 1981, Identification and nucleotide sequence of a diversity DNA segment (D) of immunoglobulin heavy-chain genes, Nature 290:562–565.PubMedCrossRefGoogle Scholar
  12. 12.
    Malcolm, S., Barton, P., Murphy, C., Ferguson-Smith, M. A., Bentley, D. L., and Rabbitts, T. H., 1982, Localization of human immunoglobulin K light chain variable region genes to the short arm of chromosome 2 by in situ hybridization, Proc. Natl. Acad. Sci. USA 79:4957–4961.PubMedCrossRefGoogle Scholar
  13. 13.
    McBride, O. W., Hieter, P. A., Hollis, G. F., Swan, D., Otey, M. C., and Leder, P., 1982, Chromosomal location of human kappa and lambda immunoglobulin light chain constant region genes, J. Exp. Med. 155:1480–1490.PubMedCrossRefGoogle Scholar
  14. 14.
    Kirsch, I. R., Morton, C. C., Nakahara, K., and Leder, P., 1982, Human immunoglobulin heavy chain genes map to a region of translocation in malignant B lymphocytes, Science 216:301–303.PubMedCrossRefGoogle Scholar
  15. 15.
    Seidman, J. G., Max, E. E., and Leder, P., 1979, A /c-immunoglobulin gene is formed by site-specific recombination without further somatic mutation, Nature 280:370–375.PubMedCrossRefGoogle Scholar
  16. 16.
    Max, E. E., Seidman, J. G., and Leder, P., 1979, Sequences of five potential recombination sites encoded close to an immunoglobulin K constant region gene, Proc. Natl. Acad. Sci. USA 76:3450–3454.PubMedCrossRefGoogle Scholar
  17. 17.
    Sakano, H., Huppi, K., Heinrich, G., and Tonegawa, S., 1979, Sequences at the somatic recombination sites of immunoglobulin light-chain genes,Nature 280:288–294.PubMedCrossRefGoogle Scholar
  18. 18.
    Taub, R., Kirsch, I., Morton, C., Lenoir, G., Swan, D., Tronick, S., Aaronson, S., and Leder, P., 1982, Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt’s lymphoma and murine plasmacytoma cells, Proc. Natl. Acad. Sci. USA 79:7837–7841.PubMedCrossRefGoogle Scholar
  19. 19.
    Ohno, S., Babonits, M., Wiener, F., Spira, J., Klein, G., and Potter, M., 1979, Nonrandom chromosome changes involving the Ig gene-carrying chromosomes 12 and 6 in pristane-induced mouse plasmacytomas, Cell 18:1001–1007.PubMedCrossRefGoogle Scholar
  20. 20.
    Bently, D. L., and Rabbitts, T. H., 1981, Human WK immunoglobulin gene number: Implications for the origin of antibody diversity, Cell 24:613–623.CrossRefGoogle Scholar
  21. 21.
    Taub, R. A., Hollis, G. F., Hieter, P. A., Korsmeyer, S. J., Waldmann, T. A., and Leder, P., 1983, The variable amplification of immunoglobulin lambda light chain genes in human populations, Nature 304:172- 174.PubMedCrossRefGoogle Scholar
  22. 22.
    Matthyssens, G., and Rabbitts, T. H., 1980, Structure and multiplicity of genes for the human immunoglobulin heavy chain variable region, Proc. Natl. Acad. Sci. USA 77:6561–6565.PubMedCrossRefGoogle Scholar
  23. 23.
    Rechavi, G., Bienz, B., Ram, D., Ben-Neriah, Y., Cohen, J. B., Zakut, R., and Givol, D., 1982, Organization and evolution of immunoglobulin VH gene subgroups, Proc. Natl. Acad. Sci. USA 79:4405–4409.PubMedCrossRefGoogle Scholar
  24. 24.
    Wu, T. T., and Kabat, E. A., 1982, Fourteen nucleotides in the second complementarity determining region of a human heavy-chain variable region gene are identical with a sequence in a human D minigene, Proc. Natl. Acad. Sci. USA 79:5031–5032.PubMedCrossRefGoogle Scholar
  25. 25.
    Korsmeyer, S. J., Hieter, P. A., Ravetch, J. V., Poplack, D. G., Waldmann, T. A., and Leder, P., 1981, Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells, Proc. Natl. Acad. Sci. USA 78:7096–7100.PubMedCrossRefGoogle Scholar
  26. 26.
    Korsmeyer, S. J., Arnold, A., Bakhshi, A., Ravetch, J. V., Siebenlist, U., Hieter, P. A., Sharrow, S. O., LeBien, T. W., Kersey, J. H., Poplack, D. G., Leder, P., and Waldmann, T. A., 1983, Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T-cell and B- cell precursor origins, J. Clin. Invest. 71:301–313.PubMedCrossRefGoogle Scholar
  27. 27.
    Alt, F. W., and Baltimore, D. 1982, Joining of immunoglobulin heavy chain gene segments: Implications from a chromosome with evidence of three D-JH fusions, Proc. Natl. Acad. Sci. USA 79:4118–4122.PubMedCrossRefGoogle Scholar
  28. 28.
    Siden, E., Alt, F. W., Shinefeld, L., Sato, V., and Baltimore, D., 1981, Synthesis of immunoglobulin µ chain gene products precedes synthesis of light chains during B-lymphocyte development, Proc. Natl. Acad. Sci. USA 78:1823–1827.PubMedCrossRefGoogle Scholar
  29. 29.
    Leder, P., Max, E. E., Seidman, J. G., Kwan, S.-P., Scharff, M., Nau, M., and Norman, B., 1980, Recombination events that activate, diversify, and delete immunoglobulin genes,Cold Spring Harbor Symp. Quant. Biol. 45:859–865.CrossRefGoogle Scholar
  30. 30.
    Hieter, P. A., Korsmeyer, S. J., Waldmann, T. A., and Leder, P., 1981, Human immunoglobulin K light- chain genes are deleted or rearranged in X-producing B cells, Nature 290:368–372.PubMedCrossRefGoogle Scholar
  31. 31.
    Korsmeyer, S. J., Hieter, P. A., Sharrow, S. O., Goldman, C. K., Leder, P., and Waldmann, T. A., 1982, Normal human B-cells display ordered light-chain gene rearrangements and deletions, J. Exp. Med. 156:975–985.PubMedCrossRefGoogle Scholar
  32. 32.
    Coleclough, C., Perry, R. P., Karjalainen, K., and Weigert, M., 1981, Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression, Nature 290:372–378.PubMedCrossRefGoogle Scholar
  33. 33.
    Alt, F. W., Enea, V., Bothwell, A. L. M., and Baltimore, D., 1980, Activity of multiple light chain genes in murine myeloma cells producing a single, functional light chain, Cell 21:1–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Davis, M. M., Kim, S. K., and Hood, L. E., 1980, DNA sequences mediating class switching in α-immunoglobulins, Science 209:1360–1365.PubMedCrossRefGoogle Scholar
  35. 35.
    Kataoka, T., Miyata, T., and Honjo, T., 1981, Repetitive sequences in class-switch recombination regions of immunoglobulin heavy chain genes, Cell 23:357–368.PubMedCrossRefGoogle Scholar
  36. 36.
    Obata, M., Kataoka, T., Nakai, S., Yamagishi, H., Takahashi, N., Yamawaki-Kataoka, Y., Nikaido, T., Shimizu, A., and Honjo, T.,1981, Structure of a rearranged γ1 chain gene and its implication to immunoglobulin class-switch mechanism, Proc. Natl. Acad. Sci. USA 78:2437–2441.PubMedCrossRefGoogle Scholar
  37. 37.
    Marcu, K. B., Lang, R. B., Stanton, L. W., and Harris, L. J., 1982, A model for the molecular requirements of immunoglobulin heavy chain class switching, Nature (London) 298:87–89.CrossRefGoogle Scholar
  38. 38.
    Ravetch, J. V., Kirsch, I. R., and Leder, P., 1980, Evolutionary approach to the question of immunoglobulin heavy chain switching: Evidence from cloned human and mouse genes, Proc. Natl. Acad. Sci. USA 77:6734–6738.PubMedCrossRefGoogle Scholar
  39. 39.
    Rabbitts, T. H., Forster, A., and Milstein, C. P., 1981, Human immunoglobulin heavy chain genes: Evolutionary comparisons of Cµ, and C, genes and associated switch sequences, Nucleic Acids Res. 9:4509- 4524.PubMedCrossRefGoogle Scholar
  40. 40.
    Knap, M. R., Liu, C.-P., Newell, N., Ward, R. B., Tucker, P. W., Strober, S., and Blattner, F., 1982, Simultaneous expression of immunoglobulin µ and heavy chains by a cloned B-cell lymphoma: A single copy of the VH gene is shared by two adjacent CH genes, Proc. Natl. Acad. Sci. USA 79:2996–3000.CrossRefGoogle Scholar
  41. 41.
    Moore, K. W., Rogers, J., Hunkapiller, T., Early, P., Nottenburg, C., Weissman, I., Bazin, H., Wall, R., and Hood, L., 1981, Expression of IgD may use both DNA rearrangement and RNA splicing mechanisms, Proc. Natl. Acad. Sci. USA 78:1800–1804.PubMedCrossRefGoogle Scholar
  42. 42.
    Flanagan, J. G., and Rabbitts, T. H., 1982, Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing γ, ɛ, µ genes,Nature 300:709–713.PubMedCrossRefGoogle Scholar
  43. 43.
    Max, E. E., Battey, J., Ney, R., Kirsch, I. R., and Leder, P., 1982, Duplication and deletion in the human immunoglobulin ɛ genes, Cell 29:691–699.PubMedCrossRefGoogle Scholar
  44. 44.
    Takahashi, N., Ueda, S., Obata, M., Nikaido, T., Nakai, S., and Honjo, T., 1982, Structure of human immunoglobulin gamma genes: Implications for evolution of a gene family, Cell 29:671–679.PubMedCrossRefGoogle Scholar
  45. 45.
    Max, E. E., Seidman, J. G., Miller, H., and Leder, P., 1980, Variation in the crossover point of kappa immunoglobulin gene V-J recombination: Evidence from a cryptic gene, Cell 21:793–799.PubMedCrossRefGoogle Scholar
  46. 46.
    Bothwell, A. L. M., Paskind, M., Reth, M., Imanishi-Kari, T., Rajewsky, K., and Baltimore, D., 1981, Heavy chain variable region contribution to the NPb family of antibodies: Somatic mutation evident in a γ2a variable region, Cell 24:625–637.PubMedCrossRefGoogle Scholar
  47. 47.
    Gearhart, P. J., Johnson, N. D., Douglas, R., and Hood, L., 1981, IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts, Nature 291:29–34.PubMedCrossRefGoogle Scholar
  48. 48.
    Pech, M., Hochtl, J., Schnell, H., and Zachau, H. G., 1981, Differences between germ-line and rearranged immunoglobulin VK coding sequences suggest a localized mutation mechainsim, Nature 291:668–670.PubMedCrossRefGoogle Scholar
  49. 49.
    Seising, E., and Storb, U., 1981, Somatic mutation of immunoglobulin light-chain variable-region genes, Cell 25:47–58.CrossRefGoogle Scholar
  50. 50.
    Early, P., Rogers, J., Davis, M., Calame, K., Bond, M., Wall, R., and Hood, L., 1980, Two mRNAs can be produced from a single immunoglobulin /x gene by alternative RNA processing pathways, Cell 20:313- 319.PubMedCrossRefGoogle Scholar
  51. 51.
    Cushley, W., Coupar, B. E. H., Mickelson, C. A., and Williamson, A. R., 1982, A common mechanism for the synthesis of membrane and secreted immunoglobulin α,γ, and µ chains, Nature 298:77–79.PubMedCrossRefGoogle Scholar
  52. 52.
    Rowley, J. D., 1980, Chromosome abnormalities in cancer, Cancer Genet. Cytogenet. 2:175–198.CrossRefGoogle Scholar
  53. 53.
    Croce, C. M., Shadner, M., Martinis, J., Cicurel, L., D’Ancona, G. G., Dolby, T. W., and Koprowski, H., 1979, Chromosomal location of the genes for human immunoglobulin heavy chains,Proc. Natl. Acad. Sci. USA 76:3416–3420.PubMedCrossRefGoogle Scholar
  54. 54.
    Lenoir, G. M., Preud’homme, J. L., Bernheim, A., and Berger, R., 1982, Correlations between immunoglobulin light chain expression and variant translocation in Burkitt’s lymphoma, Nature 298:474–476.PubMedCrossRefGoogle Scholar
  55. 55.
    Bishop, J. M., 1983, Cancer genes come of age, Cell 32:1018–1020.PubMedCrossRefGoogle Scholar
  56. 56.
    Hayward, W. S., Neel, B. G., and Astrin, S. M., 1981, Activation of a cellular one gene by promoter insertion in ALV-induced lymphoid leukosis, Nature 290:475–480.PubMedCrossRefGoogle Scholar
  57. 57.
    Erickson, J., Finan, J., Nowell, P. C., and Croce, C. M., 1982, Translocation of immunoglobulin VH genes in Burkitt lymphoma, Proc. Natl. Acad. Sci. USA 79:5611–5615.CrossRefGoogle Scholar
  58. 58.
    Nishikura, K., Ar-Rushdi, A., Erickson, J., Watt, R., Rouevco, G. and Croce, C. M., 1983, Differential expression of the normal and of the translocated human c-myc oncogenes in B cells, Proc. Natl. Acad. Sci. USA 80:4822–4826.PubMedCrossRefGoogle Scholar
  59. 59.
    Gillies, S. D., Morrison, S. L., Oi, V. T., and Tonegawa, S., 1983, A tissue specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy-chain gene, Cell 33:717–728.PubMedCrossRefGoogle Scholar
  60. 60.
    Benjamin, D., Magrath, I. T., Triche, T. J., Schroff, R. W., Jensen, J. P., and Korsmeyer, S. J., 1984, Induction of plasmacytoid differentiation by phorbol ester in B-cell lymphoma cell lines bearing 8; 14 translocations, Proc. Natl. Acad. Sci. USA (in press).Google Scholar
  61. 61.
    Arnold, A., Cossman, J., Bakhshi, A., Jaffe, E., Waldmann, T. A., and Korsmeyer, S. J., 1983, Immunoglobulin gene rearrangements as unique clonal markers in human lymphoid neoplasms, N. Engl. J. Med. 309:1593–1599.PubMedCrossRefGoogle Scholar
  62. 62.
    Bakhshi, A., Minowada, J., Arnold, A., Cossman, J., Jensen, J. P., Whang-Peng, J., Waldmann, T. A., and Korsmeyer, S. J., 1983, Lymphoid blast crises of chronic myelogenous leukemia represent stages in the development of B-cell precursors, N. Engl. J. Med. 309:826–831.PubMedCrossRefGoogle Scholar
  63. 63.
    Korsmeyer, S. J., Greene, W. C., Cossman, J., Hsu, S.-M., Jensen, J. P., Neckers, L. M., Marshall, S. L., Bakhshi, A., Depper, J. M., Leonard, W. J., Jaffe, E. S., and Waldmann, T. A., 1983, Rearrangement and expression of immunoglobulin genes and expression of Tac antigen in hairy cell leukemia, Proc. Natl. Acad. Sci. USA 80:4522–4526.PubMedCrossRefGoogle Scholar
  64. 64.
    Miller, R. A., Maloney, D. G., Warnke, R., and Levy, R., 1982, Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody, N. Engl. J. Med. 306:517–522.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Stanley J. Korsmeyer
    • 1
  • Ajay Bakhshi
    • 1
  • Andrew Arnold
    • 1
  • Katherine A. Siminovitch
    • 1
  • Thomas A. Waldmann
    • 1
  1. 1.Metabolism BranchNational Cancer InstituteBethesdaUSA

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