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.

  • Original Manuscript
  • Published:

Myeloma

Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations

Leukemia volume 14, pages 909–921 (2000)Cite this article

Abstract

DNA sequence analysis of PCR amplified Igh/c-myc junction fragments of T(12;15) chromosome translocations and immunohistochemical determination of immunoglobulin isotype production were employed to study the clonal diversification of neoplastic translocated plasma cells that resided in peritoneal inflammatory granulomas of BALB/c mice harboring primary plasmacytomas. The diversity of plasma cells was found to take two major forms when the fine structure of the T(12;15) translocation was used as the clonotypic marker. First, mosaics of clones containing translocations that were apparently unrelated to each other were detected in nine out of 17 (53%) mice. Second, subclones derived from common T(12;15)+ progenitors by either secondary deletions in translocation breakpoint regions or aberrant isotype switching near translocation breaksites were found in five of 17 (29.5%) mice. When Ig expression was utilized as the clonotypic marker, clonal mosaics were shown to occur in all mice. This was demonstrated by the finding that the prevalent IgA- or IgG-producing plasmacytoma clone was invariably accompanied by smaller clones of IgG- or IgA-expressing neoplastic plasma cells, respectively. These results provided new insights into the clonal diversification at the terminal stage of plasmacytomagenesis. In addition, they suggested that BALB/c plasmacytomas may be uniquely useful for studying clonal diversity during B cell oncogenesis, since clonal evolution can be evaluated in a pool of tumor and tumor precursor cells that is clearly defined by the T(12;15) chromosomal translocation and the production of monoclonal immunoglobulin.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Shen-Ong GL, Keath EJ, Piccoli SP, Cole MD . Novel myc oncogene RNA from abortive immunoglobulin-gene recombination in mouse plasmacytomas Cell 1982 31: 443–452

    Article  CAS  Google Scholar 

  2. Janz S, Muller J, Shaughnessy J, Potter M . Detection of recombinations between c-myc and immunoglobulin switch alpha in murine plasma cell tumors and preneoplastic lesions by polymerase chain reaction Proc Natl Acad Sci USA 1993 90: 7361–7365

    Article  CAS  Google Scholar 

  3. Potter M, MacCardle RC . Histology of developing plasma cell neoplasia induced by mineral oil in BALB/c mice J Natl Cancer Inst 1964 33: 497–515

    CAS  PubMed  Google Scholar 

  4. Potter M, Morrison S, Wiener F, Zhang XK, Miller FW . Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice J Natl Cancer Inst 1994 86: 1058–1065

    Article  CAS  Google Scholar 

  5. Müller JR, Potter M, Janz S . Differences in the molecular structure of c-myc-activating recombinations in murine plasmacytomas and precursor cells Proc Natl Acad Sci USA 1994 91: 12066–12070

    Article  Google Scholar 

  6. Müller JR, Jones GM, Potter M, Janz S . Detection of immunoglobulin/c-myc recombinations in mice that are resistant to plasmacytoma induction Cancer Res 1996 56: 419–423

    PubMed  Google Scholar 

  7. Müller JR, Jones GM, Janz S, Potter M . Migration of cells with immunoglobulin/c-myc recombinations in lymphoid tissues of mice Blood 1997 89: 291–296

    PubMed  Google Scholar 

  8. Potter M, Wax JS . Peritoneal plasmacytomagenesis in mice: comparison of different pristane dose regimens J Natl Cancer Inst 1983 71: 391–395

    CAS  PubMed  Google Scholar 

  9. Rolink A, Haasner D, Nishikawa SI, Melchers F . Changes in frequencies of clonable preB cells during life in different lymphoid organs of mice Blood 1993 81: 2290–2300

    CAS  PubMed  Google Scholar 

  10. Ehrlich A, Martin V, Müller W, Rajewsky K . Analysis of the B-cell progenitor compartment at the level of single cells Curr Biol 1994 4: 573–583

    Article  Google Scholar 

  11. Kovalchuk AL, Müller JR, Janz S . Deletional remodeling of c-myc-deregulating translocations Oncogene 1997 15: 2369–2377

    Article  CAS  Google Scholar 

  12. Müller JR, Janz S, Potter M . Differences between Burkitt's lymphomas and mouse plasmacytomas in the immunoglobulin heavy chain/c-myc recombinations that occur in their chromosomal translocations Cancer Res 1995 55: 5012–5018

    PubMed  Google Scholar 

  13. Owens JD Jr, Finkelman FD, Mountz JD, Mushinski JF . Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion Mol Cell Biol 1991 11: 5660–5670

    Article  Google Scholar 

  14. Potter M, Wiener F . Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations Carcinogenesis 1992 13: 1681–1697

    Article  CAS  Google Scholar 

  15. Baar J, Shulman MJ . The Ig heavy chain switch region is a hotspot for insertion of transfected DNA J Immunol 1995 155: 1911–1920

    CAS  PubMed  Google Scholar 

  16. Oancea AE, Tsui FW, Shulman MJ . Targeted removal of the mu switch region from mouse hybridoma cells. A test of its role in gene expression in the endogenous IgH locus J Immunol 1995 155: 5678–5683

    CAS  PubMed  Google Scholar 

  17. Baar J, Pennell NM, Shulman MJ . Analysis of a hot spot for DNA insertion suggests a mechanism for Ig switch recombination J Immunol 1996 157: 3430–3435

    CAS  PubMed  Google Scholar 

  18. Buzina A, Shulman MJ . An element in the endogenous IgH locus stimulates gene targeting in hybridoma cells Nucleic Acids Res 1996 24: 1525–1530

    Article  CAS  Google Scholar 

  19. Cogne M, Lansford R, Bottaro A, Zhang J, Gorman J, Young F, Cheng HL, Alt FW . A class switch control region at the 3′ end of the immunoglobulin heavy chain locus Cell 1994 77: 737–747

    Article  Google Scholar 

  20. Webb CF, Cooper MD, Burrows PD, Griffin JA . Immunoglobulin gene rearrangements and deletions in human Epstein–Barr virus-transformed cell lines producing different IgG and IgA subclasses Proc Natl Acad Sci USA 1985 82: 5495–5499

    Article  CAS  Google Scholar 

  21. Lewis SM, Agard E, Suh S, Czyzyk L . Cryptic signals and the fidelity of V(D)J joining Mol Cell Biol 1997 17: 3125–3136

    Article  CAS  Google Scholar 

  22. Bailey SN, Rosenberg N . Assessing the pathogenic potential of the V(D)J recombinase by interlocus immunoglobulin light-chain gene rearrangement Mol Cell Biol 1997 17: 887–894

    Article  CAS  Google Scholar 

  23. Arulampalam V, Eckhardt L, Pettersson S . The enhancer shift: a model to explain the developmental control of IgH gene expression in B-lineage cells Immunol Today 1997 18: 549–554

    Article  CAS  Google Scholar 

  24. Zhang K, Cheah HK, Saxon A . Secondary deletional recombination of rearranged switch region in Ig isotype-switched B cells. A mechanism for isotype stabilization J Immunol 1995 154: 2237–2247

    CAS  PubMed  Google Scholar 

  25. Radbruch A, Burger C, Klein S, Muller W . Control of immunoglobulin class switch recombination Immunol Rev 1986 89: 69–83

    Article  CAS  Google Scholar 

  26. Beecham EJ, Jones GM, Link C, Huppi K, Potter M, Mushinski JF, Bohr VA . DNA repair defects associated with chromosomal translocation breaksite regions Mol Cell Biol 1994 14: 1204–1212

    Article  CAS  Google Scholar 

  27. Beecham EJ, Owens JD, Shaughnessy JD Jr, Huppi K, Bohr VA, Mushinski JF . Decoupling of DNA excision repair and RNA transcription in translocation breaksite regions of plasmacytoma-susceptible BALB/cAnPt mice Carcinogenesis 1997 18: 687–694

    Article  CAS  Google Scholar 

  28. Potter M, Mushinski EB, Wax JS, Hartley J, Mock BA . Identification of two genes on chromosome 4 that determine resistance to plasmacytoma induction in mice Cancer Res 1994 54: 969–975

    CAS  PubMed  Google Scholar 

  29. Morse HC, Pumphrey JG, Potter M, Asofsky R . Murine plasma cells secreting more than one class of immunoglobulin heavy chain. I. Frequency of two or more M-components in ascitic fluids from 788 primary plasmacytomas J Immunol 1976 117: 541–547

    PubMed  Google Scholar 

  30. Potter M . Plasma cell neoplasia in a single host: a mosaic of different protein-producing cell types J Exp Med 1962 115: 339–356

    Article  CAS  Google Scholar 

  31. Tang JC, Ho FC, Chan AC, Srivastava G . Clonality of lymphomas at multiple sites in SJL mice Lab Invest 1998 78: 205–212

    CAS  PubMed  Google Scholar 

  32. Newcomb EW . Clonal evolution of N-methylnitrosourea-induced C57BL/6J thymic lymphomas by analysis of multiple genetic alterations Leukemia Res 1997 21: 189–198

    Article  CAS  Google Scholar 

  33. Habano W, Sugai T, Nakamura S . Mismatch repair deficiency leads to a unique mode of colorectal tumorigenesis characterized by intratumoral heterogeneity Oncogene 1998 16: 1259–1265

    Article  CAS  Google Scholar 

  34. Potter M, Pumphrey JG, Bailey DW . Genetics of susceptibility to plasmacytoma induction. I. BALB/cAnN (C), C57BL/6N (B6), C57BL/Ka (BK), (C times B6)F1, (C times BK)F1, and C times B recombinant-inbred strains J Natl Cancer Inst 1975 54: 1413–1417

    Article  CAS  Google Scholar 

  35. Mai S, Fluri M, Siwarski D, Huppi K . Genomic instability in MycER-activated Rat1A-MycER cells Chromos Res 1996 4: 365–371

    Article  CAS  Google Scholar 

  36. Mai S, Hanley-Hyde J, Fluri M . c-Myc overexpression associated DHFR gene amplification in hamster, rat, mouse and human cell lines Oncogene 1996 12: 277–288

    CAS  PubMed  Google Scholar 

  37. Davis CD, Dacquel EJ, Schut HA, Thorgeirsson SS, Snyderwine EG . In vivo mutagenicity and DNA adduct levels of heterocyclic amines in Muta mice and c-myc/lacZ double transgenic mice Mutat Res 1996 356: 287–296

    Article  Google Scholar 

  38. Felsher DW, Bishop JM . Transient excess of MYC activity can elicit genomic instability and tumorigenesis Proc Natl Acad Sci USA 1999 96: 3940–3944

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Michael Potter for supporting this work, sharing his expertise on the histogenesis of plasmacytoma development and making many additional helpful suggestions in the course of the experiments. We gratefully acknowledge the contributions of Wendy duBois to animal husbandry. We are grateful to Drs Lynne D Rockwood, Rebecca Liddell and J Frederic Mushinski for reading the manuscript and providing editorial assistance.

Author information

Authors and Affiliations

  1. Division of Basic Sciences, Laboratory of Genetics, National Cancer Institute, National Institutes of Health, 37 Center Drive, Bethesda, MD 20892–4255, USA

    AL Kovalchuk, EB Mushinski & S Janz

Authors
  1. AL Kovalchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. EB Mushinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Janz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kovalchuk, A., Mushinski, E. & Janz, S. Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations. Leukemia 14, 909–921 (2000). https://doi.org/10.1038/sj.leu.2401676

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401676

Keywords

This article is cited by

Search

Advanced search

Quick links