Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1990 Jul;9(7):2133–2140. doi: 10.1002/j.1460-2075.1990.tb07382.x

Sequence homologies, N sequence insertion and JH gene utilization in VHDJH joining: implications for the joining mechanism and the ontogenetic timing of Ly1 B cell and B-CLL progenitor generation.

H Gu 1, I Förster 1, K Rajewsky 1
PMCID: PMC551934  PMID: 2113468

Abstract

Sequence analysis of rearranged VHDJH genes of B lineage cells from various stages of ontogeny indicates that short sequence homologies at the breakpoints of recombination contribute to V region gene assembly. Such homologies are regularly seen at DJH junctions of neonatal pre-B cells, most of which do not contain N sequences. In the same cells, but not at later developmental stages, preferential usage of the JH1 element is observed. After birth, N sequence insertion increases with time and is always more prominent at the VHD border than the DJH border. In pre-B cells from adult animals and in mature B cells, in cases where N sequences were not detectable, sequence homologies at the DJH border were found in only half of the instances. This lower incidence could be due to N sequence addition to one of the recombining DNA ends and/or cellular selection. Inspection of VHDJH junctions for N sequence insertion, sequence homologies at the DJH border and JH1 usage allows the estimation of the timepoint in ontogeny at which particular B cell subsets are seeded into the immune system. Specifically, the present data show that the cells of the Ly1 B cell subset are generated not only neonatally but also beyond the first weeks of life. However, the DJH junctions of the progenitors of chronic B cell leukemias which originate from the same B cell subset resemble those of neonatal pre-B cells, suggesting that these cells have already undergone a transforming event at this early developmental stage.

Full text

PDF
2133

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adachi M., Tefferi A., Greipp P. R., Kipps T. J., Tsujimoto Y. Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med. 1990 Feb 1;171(2):559–564. doi: 10.1084/jem.171.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alt F. W., Baltimore D. Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4118–4122. doi: 10.1073/pnas.79.13.4118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alt F. W., Blackwell T. K., Yancopoulos G. D. Development of the primary antibody repertoire. Science. 1987 Nov 20;238(4830):1079–1087. doi: 10.1126/science.3317825. [DOI] [PubMed] [Google Scholar]
  4. Asarnow D. M., Goodman T., LeFrancois L., Allison J. P. Distinct antigen receptor repertoires of two classes of murine epithelium-associated T cells. Nature. 1989 Sep 7;341(6237):60–62. doi: 10.1038/341060a0. [DOI] [PubMed] [Google Scholar]
  5. Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
  6. Cory S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv Cancer Res. 1986;47:189–234. doi: 10.1016/s0065-230x(08)60200-6. [DOI] [PubMed] [Google Scholar]
  7. Coutinho A. Beyond clonal selection and network. Immunol Rev. 1989 Aug;110:63–87. doi: 10.1111/j.1600-065x.1989.tb00027.x. [DOI] [PubMed] [Google Scholar]
  8. Croce C. M., Nowell P. C. Molecular genetics of human B cell neoplasia. Adv Immunol. 1986;38:245–274. doi: 10.1016/s0065-2776(08)60008-5. [DOI] [PubMed] [Google Scholar]
  9. Deng G., Wu R. Terminal transferase: use of the tailing of DNA and for in vitro mutagenesis. Methods Enzymol. 1983;100:96–116. doi: 10.1016/0076-6879(83)00047-6. [DOI] [PubMed] [Google Scholar]
  10. Desiderio S. V., Yancopoulos G. D., Paskind M., Thomas E., Boss M. A., Landau N., Alt F. W., Baltimore D. Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature. 1984 Oct 25;311(5988):752–755. doi: 10.1038/311752a0. [DOI] [PubMed] [Google Scholar]
  11. Elliott J. F., Rock E. P., Patten P. A., Davis M. M., Chien Y. H. The adult T-cell receptor delta-chain is diverse and distinct from that of fetal thymocytes. Nature. 1988 Feb 18;331(6157):627–631. doi: 10.1038/331627a0. [DOI] [PubMed] [Google Scholar]
  12. Förster I., Gu H., Rajewsky K. Germline antibody V regions as determinants of clonal persistence and malignant growth in the B cell compartment. EMBO J. 1988 Dec 1;7(12):3693–3703. doi: 10.1002/j.1460-2075.1988.tb03251.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Förster I., Rajewsky K. Expansion and functional activity of Ly-1+ B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. Eur J Immunol. 1987 Apr;17(4):521–528. doi: 10.1002/eji.1830170414. [DOI] [PubMed] [Google Scholar]
  14. Förster I., Vieira P., Rajewsky K. Flow cytometric analysis of cell proliferation dynamics in the B cell compartment of the mouse. Int Immunol. 1989;1(4):321–331. doi: 10.1093/intimm/1.4.321. [DOI] [PubMed] [Google Scholar]
  15. Hayakawa K., Hardy R. R., Herzenberg L. A., Herzenberg L. A. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med. 1985 Jun 1;161(6):1554–1568. doi: 10.1084/jem.161.6.1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hayakawa K., Hardy R. R. Normal, autoimmune, and malignant CD5+ B cells: the Ly-1 B lineage? Annu Rev Immunol. 1988;6:197–218. doi: 10.1146/annurev.iy.06.040188.001213. [DOI] [PubMed] [Google Scholar]
  17. Herzenberg L. A., Stall A. M., Lalor P. A., Sidman C., Moore W. A., Parks D. R., Herzenberg L. A. The Ly-1 B cell lineage. Immunol Rev. 1986 Oct;93:81–102. doi: 10.1111/j.1600-065x.1986.tb01503.x. [DOI] [PubMed] [Google Scholar]
  18. Holmberg D., Andersson A., Carlsson L., Forsgren S. Establishment and functional implications of B-cell connectivity. Immunol Rev. 1989 Aug;110:89–103. doi: 10.1111/j.1600-065x.1989.tb00028.x. [DOI] [PubMed] [Google Scholar]
  19. Ichihara Y., Hayashida H., Miyazawa S., Kurosawa Y. Only DFL16, DSP2, and DQ52 gene families exist in mouse immunoglobulin heavy chain diversity gene loci, of which DFL16 and DSP2 originate from the same primordial DH gene. Eur J Immunol. 1989 Oct;19(10):1849–1854. doi: 10.1002/eji.1830191014. [DOI] [PubMed] [Google Scholar]
  20. Kipps T. J., Tomhave E., Chen P. P., Carson D. A. Autoantibody-associated kappa light chain variable region gene expressed in chronic lymphocytic leukemia with little or no somatic mutation. Implications for etiology and immunotherapy. J Exp Med. 1988 Mar 1;167(3):840–852. doi: 10.1084/jem.167.3.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kocks C., Rajewsky K. Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol. 1989;7:537–559. doi: 10.1146/annurev.iy.07.040189.002541. [DOI] [PubMed] [Google Scholar]
  22. Kudo A., Sakaguchi N., Melchers F. Organization of the murine Ig-related lambda 5 gene transcribed selectively in pre-B lymphocytes. EMBO J. 1987 Jan;6(1):103–107. doi: 10.1002/j.1460-2075.1987.tb04725.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kurosawa Y., Tonegawa S. Organization, structure, and assembly of immunoglobulin heavy chain diversity DNA segments. J Exp Med. 1982 Jan 1;155(1):201–218. doi: 10.1084/jem.155.1.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Köhler G., Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495–497. doi: 10.1038/256495a0. [DOI] [PubMed] [Google Scholar]
  25. Lafaille J. J., DeCloux A., Bonneville M., Takagaki Y., Tonegawa S. Junctional sequences of T cell receptor gamma delta genes: implications for gamma delta T cell lineages and for a novel intermediate of V-(D)-J joining. Cell. 1989 Dec 1;59(5):859–870. doi: 10.1016/0092-8674(89)90609-0. [DOI] [PubMed] [Google Scholar]
  26. Lafaille J. J., Haas W., Coutinho A., Tonegawa S. Positive selection of gamma delta T cells. Immunol Today. 1990 Mar;11(3):75–78. doi: 10.1016/0167-5699(90)90030-d. [DOI] [PubMed] [Google Scholar]
  27. Lalor P. A., Stall A. M., Adams S., Herzenberg L. A. Permanent alteration of the murine Ly-1 B repertoire due to selective depletion of Ly-1 B cells in neonatal animals. Eur J Immunol. 1989 Mar;19(3):501–506. doi: 10.1002/eji.1830190314. [DOI] [PubMed] [Google Scholar]
  28. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  29. Loh E. Y., Elliott J. F., Cwirla S., Lanier L. L., Davis M. M. Polymerase chain reaction with single-sided specificity: analysis of T cell receptor delta chain. Science. 1989 Jan 13;243(4888):217–220. doi: 10.1126/science.2463672. [DOI] [PubMed] [Google Scholar]
  30. McCoy M. S., Toole J. J., Cunningham J. M., Chang E. H., Lowy D. R., Weinberg R. A. Characterization of a human colon/lung carcinoma oncogene. Nature. 1983 Mar 3;302(5903):79–81. doi: 10.1038/302079a0. [DOI] [PubMed] [Google Scholar]
  31. Meek K., Hasemann C., Pollok B., Alkan S. S., Brait M., Slaoui M., Urbain J., Capra J. D. Structural characterization of antiidiotypic antibodies. Evidence that Ab2s are derived from the germline differently than Ab1s. J Exp Med. 1989 Feb 1;169(2):519–533. doi: 10.1084/jem.169.2.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nishikawa S., Sasaki Y., Kina T., Amagai T., Katsura Y. A monoclonal antibody against Igh6-4 determinant. Immunogenetics. 1986;23(2):137–139. doi: 10.1007/BF00377976. [DOI] [PubMed] [Google Scholar]
  33. Pennell C. A., Arnold L. W., Haughton G., Clarke S. H. Restricted Ig variable region gene expression among Ly-1+ B cell lymphomas. J Immunol. 1988 Oct 15;141(8):2788–2796. [PubMed] [Google Scholar]
  34. Pfeiffer P., Vielmetter W. Joining of nonhomologous DNA double strand breaks in vitro. Nucleic Acids Res. 1988 Feb 11;16(3):907–924. doi: 10.1093/nar/16.3.907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pillai S., Baltimore D. Formation of disulphide-linked mu 2 omega 2 tetramers in pre-B cells by the 18K omega-immunoglobulin light chain. Nature. 1987 Sep 10;329(6135):172–174. doi: 10.1038/329172a0. [DOI] [PubMed] [Google Scholar]
  36. Reth M. G., Alt F. W. Novel immunoglobulin heavy chains are produced from DJH gene segment rearrangements in lymphoid cells. 1984 Nov 29-Dec 5Nature. 312(5993):418–423. doi: 10.1038/312418a0. [DOI] [PubMed] [Google Scholar]
  37. Reth M. G., Jackson S., Alt F. W. VHDJH formation and DJH replacement during pre-B differentiation: non-random usage of gene segments. EMBO J. 1986 Sep;5(9):2131–2138. doi: 10.1002/j.1460-2075.1986.tb04476.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Roth D. B., Wilson J. H. Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol Cell Biol. 1986 Dec;6(12):4295–4304. doi: 10.1128/mcb.6.12.4295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rothenberg E., Triglia D. Clonal proliferation unlinked to terminal deoxynucleotidyl transferase synthesis in thymocytes of young mice. J Immunol. 1983 Apr;130(4):1627–1633. [PubMed] [Google Scholar]
  40. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  41. Sakaguchi N., Melchers F. Lambda 5, a new light-chain-related locus selectively expressed in pre-B lymphocytes. Nature. 1986 Dec 11;324(6097):579–582. doi: 10.1038/324579a0. [DOI] [PubMed] [Google Scholar]
  42. Sakano H., Hüppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 1979 Jul 26;280(5720):288–294. doi: 10.1038/280288a0. [DOI] [PubMed] [Google Scholar]
  43. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Early restriction of the human antibody repertoire. Science. 1987 Nov 6;238(4828):791–793. doi: 10.1126/science.3118465. [DOI] [PubMed] [Google Scholar]
  44. Shlomchik M., Mascelli M., Shan H., Radic M. Z., Pisetsky D., Marshak-Rothstein A., Weigert M. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med. 1990 Jan 1;171(1):265–292. doi: 10.1084/jem.171.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Tarlinton D., Stall A. M., Herzenberg L. A. Repetitive usage of immunoglobulin VH and D gene segments in CD5+ Ly-1 B clones of (NZB x NZW)F1 mice. EMBO J. 1988 Dec 1;7(12):3705–3710. doi: 10.1002/j.1460-2075.1988.tb03253.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Thode S., Schäfer A., Pfeiffer P., Vielmetter W. A novel pathway of DNA end-to-end joining. Cell. 1990 Mar 23;60(6):921–928. doi: 10.1016/0092-8674(90)90340-k. [DOI] [PubMed] [Google Scholar]
  47. Vakil M., Kearney J. F. Functional characterization of monoclonal auto-anti-idiotype antibodies isolated from the early B cell repertoire of BALB/c mice. Eur J Immunol. 1986 Sep;16(9):1151–1158. doi: 10.1002/eji.1830160920. [DOI] [PubMed] [Google Scholar]
  48. Vakil M., Sauter H., Paige C., Kearney J. F. In vivo suppression of perinatal multispecific B cells results in a distortion of the adult B cell repertoire. Eur J Immunol. 1986 Sep;16(9):1159–1165. doi: 10.1002/eji.1830160921. [DOI] [PubMed] [Google Scholar]
  49. Winter E., Radbruch A., Krawinkel U. Members of novel VH gene families are found in VDJ regions of polyclonally activated B-lymphocytes. EMBO J. 1985 Nov;4(11):2861–2867. doi: 10.1002/j.1460-2075.1985.tb04015.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Yunis J. J., Frizzera G., Oken M. M., McKenna J., Theologides A., Arnesen M. Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. N Engl J Med. 1987 Jan 8;316(2):79–84. doi: 10.1056/NEJM198701083160204. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES