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Genetic Recombinations Between c-myc and Ighμ as Precursors for Recombinations Between c-myc and Ighα in BALB/c Plasmacytomas

  • S. Janz
  • A. L. Kovalchuk
  • J. R. Müller
  • M. Potter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 224)

Abstract

In this paper we present evidence that primary plasmacytomas harboring a balanced chromosomal translocation t(12;15) may consist of a mosaic of neoplastic clones of tumor cells, in which some of the clones are derived from common progenitors by large additional deletions which alter or “remodel” the fine structure of the t(12;15) on the c-myc-deregulating chromosome. This finding is based on the molecular analysis of the t(12;15) in three plasmacytomas, TEPC 1194, PCT 4127 and PCT 4132, in which primary clones of tumor cells with recombinations between the Ig heavy-chain (Igh) μ locus (Ighμ) and c-myc were found to be related to secondary clones of tumor cells with recombinations between the Igh a locus (Igha) and c-myc. Clonal relatedness was based on unique junction fragments between Sμ and c-myc that were found to be identical in Ighμ/c-myc and Ighα/c-myc breakpoint regions. Sμ/c-myc breakpoints with adjoining sequences can thus be used as clonotypic markers, providing molecular fingerprints for the evolution of precursor cells with Ighμ/c-myc recombinations into progenitor cells with Igha/c-myc recombinations. We propose that aberrant isotype switch recombination or illegitimate rearrangement in switch regions converts Ighμ/c-myc rearrangements, which are found very rarely in established plasmacytomas, into Ighα/c-myc rearrangements, which are present in about 80% of plasmacytomas with t(12;15). Remodeling of the t(12;15) results in closer juxtaposition of c-myc to the 3’-Cα locus control region and probably in enhanced transcription of c-myc. We suggest that remodeling of c-myc-deregulating rearrangements constitutes a noveln progression mechanism in malignant B-cell development.

Keywords

Enhancer Element Locus Control Region Class Switch Recombination Switch Region Breakpoint Region 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Bard JA, Birshtein BK (1995) Rearrangement of a VH-associated LINE-1 element with the expressed IgH cluster in a murine myeloma cell line. J Immunol 154:201–208PubMedGoogle Scholar
  2. 2.
    Coffman RL, Lebman DA, Rothman P (1993) Mechanism and regulation of immunoglobulin isotype switching. Adv Immunol 54:229–270PubMedCrossRefGoogle Scholar
  3. 3.
    Crossen PE, Kennedy MA, Heaton DC, Morrison MJ (1993) Cloning and sequencing of a t(14;19) breakpoint that involves the Cμ switch region. Genes Chromosomes Cancer 8:60–62PubMedCrossRefGoogle Scholar
  4. 4.
    Dunnick W, Hertz GZ, Scappino L, Gritzmacher C (1993) DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res 21:365–372PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Elenich LA, Dunnick WA (1991) Sequence at insertion site of E.Tn retrotransposon into an immunoglobulin switch region suggests a role for switch recombinase. Nucleic Acids Res 19:396PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Gerstein RM, Frankel WN, Hsieh CL, Durdik JM, Rath S, Coffin JM, Nisonoff A, Scising E (1990) Isotype switching of an immunoglobulin heavy chain transgene occurs by DNA recombination between different chromosomes. Cell 63:537–548PubMedCrossRefGoogle Scholar
  7. 7.
    Harriman W, Volk H, Defranoux N, Wabl M (1993) Immunoglobulin class switch recombination. Annu Rev Immunol 11:361–384PubMedCrossRefGoogle Scholar
  8. 8.
    Janz S, Müller J, Shaughnessy J, Potter M (1993) Detection of recombinations between c-myc and immunoglobulin switch a in murine plasma cell tumors and preneoplastic lesions by polymerase chain reaction. Proc Natl Acad Sci USA 90:7361–7365PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Knight KL, Kingzette M, Crane MA, Zhai SK (1995) Transchromosomally derived Ig heavy chains. J Immunol 155:684–691PubMedGoogle Scholar
  10. 10.
    Kottmann AH, Zevnik B, Weite M, Nielsen PJ, Köhler G (1994) A second promoter and enhancer element within the immunoglobulin heavy chain locus. Eur J Immunol 24:817–821PubMedCrossRefGoogle Scholar
  11. 11.
    Kovalchuk AL, Potter M, Janz S (1996) DNA sequence analysis of the genetic recombination between Igh6 and Myc in an uncommon BALB/c plasmacytoma, TEPC 1194. Immunogenetics 44:151–156PubMedCrossRefGoogle Scholar
  12. 12.
    Madisen L, Groudine M (1994) Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt’s lymphoma cells. Genes Dev 8:2212–2226PubMedCrossRefGoogle Scholar
  13. 13.
    Mautner J, Joos S, Werner T, Eick D, Bornkamm GW, Polack A (1995) Identification of two enhancer elements downstream of the human c-myc gene. Nucleic Acids Res 23:72–80PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Mautner J, Behrends U, Hortnagel K, Brielmeier M, Hammerschmidt W, Strobl L, Bornkamm GW (1996) c-myc expression is activated by the immunoglobulin kappa-enhancers from a distance of at least 30 kb but not by elements located within 50 kb of the unaltered c-myc locus in vivo. Oncogene 12:1299–1307PubMedGoogle Scholar
  15. 15.
    Michaelson JS, Giannini SL, Birshtein BK (1995) Identification of 3’α-hs4, a novel Ig heavy chain enhancer element regulated at multiple stages of B cell differentiation. Nucleic Acids Res 23:975–981PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Müller JR, Potter M, Janz S (1994) Differences in the molecular structure of c-myc-activating recombinations in murine plasmacytomas and precursor cells. Proc Natl Acad Sci USA 91:12066–12070PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Müller JR, Janz S, Potter M (1995) Differences between Burkitt’s lymphomas and mouse plasmacytomas in the immunoglobulin heavy chain/c-myc recombinations that occur in their chromosomal translocations. Cancer Res 55:5012–5018PubMedGoogle Scholar
  18. 18.
    Packham G, Cleveland JL (1995) c-Myc and apoptosis. Biochim Biophys Acta 1242:11–28PubMedGoogle Scholar
  19. 19.
    Pear WS, Nelson SF, Axelson H, Wahlstrom G, Bazin H, Klein G, Sumegi J. (1988) Aberrant class switching juxtaposes c-myc with a middle repetitive element (LINE) and an IgH intron in two spontaneously arising rat immunocytomas. Oncogene 2:499–507PubMedGoogle Scholar
  20. 20.
    Potter M, Wiener F (1992) Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13:1681–1697PubMedCrossRefGoogle Scholar
  21. 21.
    Sigurdardottir D, Sohn J, Kass J, Scising E (1995) Regulatory regions 3’ of the immunoglobulin heavy chain intronic enhancer differentially affect expression of a heavy chain transgene in resting and activated B cells. J Immunol 154:2217–2225PubMedGoogle Scholar
  22. 22.
    Zelenetz AD, Cleary ML, Levy R (1993) A submicroscopic interstitial deletion of chromosome 14 frequently occurs adjacent to the t(14;18) translocation breakpoint in human follicular lymphoma. Genes Chromosom Cancer 6:140–150PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • S. Janz
    • 1
  • A. L. Kovalchuk
    • 1
  • J. R. Müller
    • 1
  • M. Potter
    • 1
  1. 1.Laboratory of Genetics, Division of Basic Sciences, NCINIHBethesdaUSA

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