B-lymphocyte-lineage Cells from Early Precursors to Ig-secreting Plasma Cells: Targets of Regulation by the myc/mad/max Families of Genes?

  • F. Melchers
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 224)


Up- and down-regulation of the expression of c-myc, together or against its partners of the myc/mad/max gene families and the more recently discovered miz-1 (see papers in this volume, in particular Austen et al., Schneider et al., Schreiber-Agus et al.), is thought to control expression of genes involved in the proliferation and differentiation of cells. Very few lineages of cellular development have been studied in vivo and in vitro in comparable detail as B-lineage cells have at many different stages from an early precursor cell to the final stage of an Ig-secreting plasma cell (see [Chen and Alt 1993, Cumano et al 1992, Cumano et al 1994, Decker et al 1991, Era et al 1994, Hardy 1992, Hardy et al 1994, Hayashi et al 1990, Kincade et al 1994, Löffert et al 1994, Nossal 1994, Osmond 1991, Rajewsky 1992, Rolink et al 1994a] for a collection of relevant references). Deregulation of c-myc expression occurs as a consequence of chromosomal translocations to the IgH- and L-chain J segments which are frequently found in human Burkitt’s lymphomas, or to the IgH switch regions which are detected in mineral oil-induced mouse plasmacytomas [Potter and Wiener 1992, Shen-Ong et al 1982]. This signifies the importance of the control of expression of the myc/mad/max-gene families in normal and neoplastic B-lymphocyte development.


Secondary Lymphoid Organ Lymphocyte Development preB Cell Early Precursor Cell Chain Allele 
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  1. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD, Brinster RL (1985) The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538PubMedCrossRefGoogle Scholar
  2. Andersson J, Bullock WW, Melchers F (1974) Inhibition of mitogen stimulation of mouse lymphocytes by anti-mouse immunoglobulin antibodies. I. Mode of action. Eur J Immunol 4: 715–722PubMedCrossRefGoogle Scholar
  3. Andersson J, Coutinho A, Lernhardt W, Melchers F (1977) Clonal growth and maturation to immunoglobulin secretion in vitro of every growth-inducible B lymphocyte. Cell 10: 27–34PubMedCrossRefGoogle Scholar
  4. Andersson J, Melchers F (1974) Maturation of mitogen-activated bone marrow-derived lymphocytes in the absence of proliferation. Eur J Immunol 4: 533–539PubMedCrossRefGoogle Scholar
  5. Andersson J, Melchers F, Rolink A (1995) Stimulation by T cell independent antigens can relieve the arrest of differentiation of immature auto-reactive B cells in the bone marrow. Scand J Immunol 42: 21–33PubMedCrossRefGoogle Scholar
  6. Armitage RJ, Alderson MR (1995) B-cell stimulation. Curr Opin Immunol 7: 243–247PubMedCrossRefGoogle Scholar
  7. Benhamou LE, Cazenave PA, Sarthou P (1990) Anti-immunoglobulins induce death by apoptosis in WEHI-231 B-lymphoma cells. Eur J Immunol 20Google Scholar
  8. Chen C, Nagy Z, Prak EL, Weigert M (1995b) Immunoglobulin heavy chain gene replacement: A mechanism of receptor editing. Immunity 3: 747–755PubMedCrossRefGoogle Scholar
  9. Chen C, Nagy Z, Radic MZ, Hardy RR, Huszar D, Camper SA, Weigert M (1995a) The site and stage of anti-DNA B-cell deletion. Nature 373: 252–255PubMedCrossRefGoogle Scholar
  10. Chen J, Alt F (1993) Gene rearrangement and B-cell development. Curr Op Immunol 5: 194–200CrossRefGoogle Scholar
  11. Cumano A, Kee BL, Ramsden DA, Marshall A, Paige CJ, Wu GE (1994) Development of B lymphocytes from lymphoid committed and uncommitted progenitors. In Immunol. Rev., G Möller, ed. Munksgaard (Copenhagen), pp. 5–33Google Scholar
  12. Cumano A, Paige CJ, Iscove NN, Brady G (1992) Bipotential precursors of B cells and macrophages in murine fetal liver. Nature 356: 612–615PubMedCrossRefGoogle Scholar
  13. Decker DJ, Boyle NE, Koziol JA, Klinman NR (1991) The expression of the Ig H chain repertoire in developing bone marrow B lineage cells. J Immunol 146: 350–361PubMedGoogle Scholar
  14. Ehlich A, Matin V, Müller W, Rajewsky K (1994) Analysis of the B-cell progenitor compartment at the level of single cells. Curr Biol 4: 573–583PubMedCrossRefGoogle Scholar
  15. Era T, Nishikawa S, Sudo T, Fu-Ho W, Ogawa M, Kunisada T, Hayashi S-I, Nishikawa S-I (1994) How B-precursor cells are driven to cycle. In Immunol. Rev., G Möller, ed. Munksgaard (Copenhagen), pp. 35–51Google Scholar
  16. Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gpl30: involvement of STST3 in anti-apoptosis. Immunity 5: 449–460PubMedCrossRefGoogle Scholar
  17. Fukuda T, Kitamura D, Taniuchi I, Maekawa Y, Benhamou LE, Sarthou P, Watanabe T (1995) Restoration of surface IgM-mediated apoptosis in an anti-IgM-resistant variant of WEHI-231 lymphoma cells by HSI, a protein-tyrosine kinase substrate. Proc Natl Acad Sci 92: 7302–7306PubMedCentralPubMedCrossRefGoogle Scholar
  18. Ghia P, Gratwohl A, Signer E, Winkler TH, Melchers F, Rolink AG (1995) Immature B cells from human and mouse bone marrow can change their surface light chain expression. Eur J Immunol 25: 3108–3114PubMedCrossRefGoogle Scholar
  19. Ghia P, ten Boekel E, Sanz E, de la Hera A, Rolink A, Melchers F (1996) 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 184: 2217–2229PubMedCentralPubMedCrossRefGoogle Scholar
  20. Goodnow CC, Cyster JG, Hartley SZ, Bell SE, Cooke MP, Healy JL, Akkaraju S, Rathmell JC, Pogue SL, Shokat KP (1995) Self-tolerance checkpoints in B lymphocyte development. In Advances in Immunology, FJ Dixon, ed. Academic Press (London), pp. 279–368Google Scholar
  21. Grawunder U, Haasner D, Melchers F, Rolink A (1993) Rearrangement and expression of κ light chain genes can occur without µ heavy chain expression during differentiation of pre-B cells. Int Immunol 5: 1609–1618PubMedCrossRefGoogle Scholar
  22. Grawunder U, Leu TMJ, Schatz DG, WErner A, Rolink AG, Melchers F, Winkler TH (1995) Down-regulation of RAG1 and RAG2 gene expression in preB cells after functional immunoglobulin heavy chain rearrangement. Immunity 3: 601–608PubMedCrossRefGoogle Scholar
  23. Hardy RR (1992) Variable gene usage, physiology and development of Lyl+ (CD5+) B cells. Curr Op In Immunol 4: 181–185CrossRefGoogle Scholar
  24. Hardy RR, Carmack CE, Li YS, Hayakawa K (1994) Distinctive developmental origins and specificities of murine CD5+ B cells. In Immunol. Rev., G Möller, ed. Munksgaard (Copenhagen), pp. 91–118Google Scholar
  25. Hasbold J, Klaus GGB (1990) Anti-immunoglobulin antibodies induce apoptosis in immature B-cell lymphomas. Eur J Immunol 20: 1685–1690PubMedCrossRefGoogle Scholar
  26. Hathcock KS, Hodes RJ (1996) Role of the CD28-B7 costimulatory pathways in T cell-dependent B cell responses. In Advances in Immunology, FJ Dixon, ed. Academic Press (London), pp. 131–166Google Scholar
  27. Hayashi S, Kunisada T, Ogawa M, Sudo T, Kodama H, Suda T, Nishikawa S, Nishikawa S (1990) Stepwise progression of B lineage differentiation supported by interleukin 7 and other stromal cell molecules. J Exp Med 171: 1683–1695PubMedCrossRefGoogle Scholar
  28. Kelly K, Cochran B, Stiles C, Leder P (1984) The regulation of c-myc by growth signals. Curr Top Microbiol Immunol 113: 117–126PubMedGoogle Scholar
  29. Kincade PW, Medina KL, Smithson G (1994) Sex hormones as negative regulators of lymphopoiesis. In Immunol. Rev., G Möller, ed. Munksgaard (Copenhagen), pp. 119–134Google Scholar
  30. Kleinfeld R, Hardy RR, Tarlington D, Dangl J, Herzenberg LA, Weigert M (1986) Recombination between an expressed immunoglobulin heavy chain gene and a germ-line variable gene segment in Ly1+ Be cell lymphoma. Nature 322: 843–846CrossRefGoogle Scholar
  31. Lane P (1996) Development of B-cell memory and effector function. Curr Opin Immunol 8: 331–335PubMedCrossRefGoogle Scholar
  32. Law C-L, Clark EA (1994) Cell-cell interactions that regulate the development of B-lineage cells. Curr Opin Immunol 6: 238–247PubMedCrossRefGoogle Scholar
  33. Lernhardt W, Karasuyama H, Rolink A, Melchers F (1987) Control of the cell cycle of murine B lymphocytes: The nature of ****- and ß-B-cell growth factors and of B-cell maturation factors. Immunol Rev 99: 241–262PubMedCrossRefGoogle Scholar
  34. Löffert D, Schaal S, Ehlich A, Hardy RR, Zou Y-R, Müller W, Rajewsky K (1994) Early B-cell development in the mouse: Insights from mutations introduced by gene targeting. In Immunol. Rev., G Möller, ed. Munksgaard (Copenhagen), pp. 135–153Google Scholar
  35. Melchers F (1979) Three waves of B lymphocyte development during embryonic development in the mouse. In Cell lineage, stem cells and cell determination. INSERM Symposium 10, N le Douarin, ed. Elsevier Science Publishers (Amsterdam), pp. 281–289Google Scholar
  36. Melchers F (1995) The role of B cell and pre-B-cell receptors in development and growth control of the B-lymphocyte cell lineage. In Immunglobulin genes, T Honjo and FW Alt, eds. Academic Press (London)Google Scholar
  37. Melchers F, Andersson J, Lernhardt W, Schreier MH (1980) H-2–unrestricted polyclonal maturation without replication of small B cells induced by antigen-activated T cell help factors. Eur J Immunol 10: 679–685PubMedCrossRefGoogle Scholar
  38. Melchers F, Karasuyama H, Haasner D, Bauer S, Kudo A, Sakaguchi N, Jameson B, Rolink A (1993) The surrogate light chain in B-cell development. Immunol Today 14: 60–68PubMedCrossRefGoogle Scholar
  39. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE (1992) RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877PubMedCrossRefGoogle Scholar
  40. Mond J J, Vos Q, Lees A, Snapper CM (1995) T cell independent antigens. Curr Opin Immunol 7: 349–354PubMedCrossRefGoogle Scholar
  41. Nemazee D, Russell D, Arnold B, Haemmerling G, Allison J, Miller JF, Morahan G, Buerki K (1991) Clonal deletion of autospecific B lymphocytes. Immunol Rev 122: 117–132PubMedCrossRefGoogle Scholar
  42. Nossal GJV (1994) Differentiation of the secondary B-lymphocyte repertoire: The germinal center reaction. In Immunol. Rev., G Möller, ed. Munksgaard (Copenhagen), pp. 173–183Google Scholar
  43. Oettinger MA, Schatz DG, Gorka C, Baltimore D (1990) RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248: 1517–1523PubMedCrossRefGoogle Scholar
  44. Ogawa M, Matzusaki Y, Nishikawa S, Hayashi SI, Kunisada T, Sudo T, Kina T, Nakauchi H, Nishikawa SI (1991) Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med 174: 63–70PubMedCrossRefGoogle Scholar
  45. Oka Y, Rolink AG, Andersson J, Kamanaka M, Uchida J, Yasui T, Kishimoto T, Kikutani H, Melchers F (1996) Profound reduction of mature B cell numbers, reactivities and serum immunoglobulin levels in mice which simultaneously carry the XID and CD40–deficiency genes. Int Immunol 8: 1675–1685PubMedCrossRefGoogle Scholar
  46. Osmond DG (1991) Proliferation kinetics and the lifespan of B cells in central and peripheral lymphoid organs. Curr Opin Immunol 3: 179–185PubMedCrossRefGoogle Scholar
  47. Potter M, Wiener F (1992) Plasmactyomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13: 1681–1697PubMedCrossRefGoogle Scholar
  48. Prak EL, Weigert M (1995) Light chain replacement: A new model for antibody gene rearrangement. J Exp Med 182: 541–548PubMedCrossRefGoogle Scholar
  49. Rajewsky K (1992) Early and late B-cell development in the mouse. Curr Opin Immunol 4: 171–176PubMedCrossRefGoogle Scholar
  50. Reth M, Gehrmann P, Petrac E, Wiese P (1986) A novel VH to VHDJH joining mechanism in heavy-chain-negative (null) preB cells results in heavy-chain production. Nature 322: 840–842PubMedCrossRefGoogle Scholar
  51. Rolink A, Grawunder U, Haasner D, Strasser A, Melchers F (1993a) Immature surface Ig+ B cells can continue to rearrange K and X L chain gene loci. J Exp Med 178: 1263–1270PubMedCrossRefGoogle Scholar
  52. Rolink A, Grawunder U, Winkler TH, Karasuyama H, Melchers F (1994b) IL-2 receptor a chain (CD25, TAC) expression defines a crucial stage in preB cell development. Int Immunol 6: 1257–1264PubMedCrossRefGoogle Scholar
  53. Rolink A, Haasner D, Nishikawa SI, Melchers F (1993b) Changes in frequencies of clonable preB cells during life in different lymphoid organs of mice. Blood 81: 2290–2300PubMedGoogle Scholar
  54. Rolink A, Karasuyama H, Haasner D, Grawunder U, Martensson IL, Kudo A, Melchers F (1994a) Two pathways of B lymphocyte development in mouse bone marrow and the roles of surrogate L chain in this development. In Immunological Reviews, G Möller, ed. Munksgaard (Copenhagen), pp. 185–201Google Scholar
  55. Rolink A, Kudo A, Karasuyama H, Kikuchi Y, Melchers F (1991a) Long-term proliferating early pre B cell lines and clones with the potential to develop to surface-Ig positive mitogen-reactive B cells in vitro and in vivo. EMBO J 10: 327–336PubMedCentralPubMedGoogle Scholar
  56. Rolink A, Streb M, Nishikawa SI, Melchers F (1991b) The c-kit encoded tyrosine kinase regulates the proliferation of early pre-B cells. Eur J Immunol 21: 2609–2612PubMedCrossRefGoogle Scholar
  57. Rolink A, ten Boekel E, Melchers F, Fearon DT, Krop I, Andersson J (1996a) A subpopulation of B220+ cells in murine bone marrow does not express CD 19 and contains NK cell-progenitors. J Exp Med 183: 187–194PubMedCrossRefGoogle Scholar
  58. Rolink AG, Melchers F, Andersson J (1996b) The SCID but not the RAG2 gene product is required for Sµ-Sε-heavy chain class switching. Immunity 5: 319–330PubMedCrossRefGoogle Scholar
  59. Schatz DG, Oettinger MA, Baltimore D (1989) The V(D)J recombination activating gene, RAG-1. Cell 59: 1035–1048PubMedCrossRefGoogle Scholar
  60. Scott DW, Livnat D, Pennell CA, Keng P (1996) Lymphoma models for B-cell activation and tolerance III. Cell cycle dependence for negative signalling of WEHI-231 B lymphoma cells by anti-µ. J Exp Med 164: 156–164CrossRefGoogle Scholar
  61. Shen-Ong GLC, Keath E, Picolli SP, Cole MD (1982) Novel myc oncogene RNA from abortive immunoglobulin gene recombination in mouse plasmacytomas. Cell 31: 443–452PubMedCrossRefGoogle Scholar
  62. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, Alt FW (1992) RAG-2–deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68: 855–867PubMedCrossRefGoogle Scholar
  63. Snapper CM, Rosas FR, Zelazowski P, Moorman MA, Kehry MR, Bravo R, Weih F (1996) B cells lacking Re IB are defective in proliferative responses, but undergo normal B cell maturation to Ig secretaion and Ig class switching. J Exp Med 184: 1537–1541PubMedCrossRefGoogle Scholar
  64. Stavnezer J (1996) Immunoglobulin class switching. Curr Opin Immunol 8: 199–205PubMedCrossRefGoogle Scholar
  65. Storb U (1996) The molecular basis of somatic hypermutation of immunoglobulin genes. Curr Opin Immunol 8: 206–213PubMedCrossRefGoogle Scholar
  66. Strasser A, Wittingham S, Vaux DL, Bath ML, Adams JM, Cory S, Harris AW (1991) Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci USA 88: 8661–8665PubMedCentralPubMedCrossRefGoogle Scholar
  67. ten Boekel E, Melchers F, Rolink A (1995) The status of Ig loci rearrangements in single cells from different stages of B cell development. Int Immunol 7: 1013–1019PubMedCrossRefGoogle Scholar
  68. Winkler TH, Melchers F, Rolink AG (1994) Interleukin-3 and interleukin-7 are alternative growth factors for the same B-cell precursors in the mouse. Blood 85: 2045–2051Google Scholar
  69. Young F, Ardman B, Shinkai Y, Lansford R, Blackwell TK, Mendelsohn M, Rolink A, Melchers F, Alt FW (1994) Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation. Genes Dev 8: 1043–1057PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • F. Melchers
    • 1
  1. 1.Basel Institute for ImmunologyBaselSwitzerland

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