Point mutations in the c–Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas (original) (raw)

Nature Genetics volume 5, pages 56–61 (1993)Cite this article

Abstract

We have screened the entire coding region of c–myc in a panel of Burkitt's lymphomas (BLs) and mouse plasmacytomas (PCTs). Contrary to the belief that c–myc is wild type in these tumours, we found that 65% of 57 BLs and 30% of 10 PCTs tested exhibit at least one amino acid (aa) substitution. These mutations were apparently homozygous in all BL cell lines tested and two tumour biopsies, implying that the mutations often occur before Myc/lg translocation in BL. In PCTs, only the mutant c–myc allele was expressed indicating a functional homozygosity, but occurrence of mutations after the translocation. Many of the observed mutations are clustered in regions associated with transcriptional activation and apoptosis, and in BLs, they frequently occur at sites of phosphorylation, suggesting that the mutations have a pathogenetic role.

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References

  1. Marcu, K.B., Bossone, S.A. & Patel, A.J. Myc function and regulation. Ann. Rev. Biochem. 61, 809–860 (1992).
    Article CAS Google Scholar
  2. Prendergast, G.C. & Ziff, E.B. A new bind for myc. Trends Genet. 8, 91–96 (1992).
    Article CAS Google Scholar
  3. Depinho, R.A., Schreiber-Agus, N. & Alt, F.W. Myc family oncogenes in the development of normal and neoplastic cells. Adv. cancer Res. 57, 1–46 (1991).
    Article CAS Google Scholar
  4. Cole, M. The myc oncogene: its role in transformation and differentiation. Adv. cancer Res. 20, 361–384 (1986).
    CAS Google Scholar
  5. Potter, M. & Wiener, F. Plasmacytomagenesis in mice: model; model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13, 1681–1697 (1992).
    Article CAS Google Scholar
  6. Magrath, I. The pathogenesis of Burkitt's lymphoma. Adv. cancer Res. 55, 133–270 (1990).
    Article CAS Google Scholar
  7. Evan, G.I. et al. Induction of apoptosis in fibroblasts by c–Myc protein. Cell 69, 119–128 (1992).
    Article CAS Google Scholar
  8. Wyllie, A.H. et al. Rodent fibroblast tumours expressing human myc and ras genes: growth, metastasis and endogenous oncogene expression. Br. J. Cancer 56, 251–259 (1987).
    Article CAS Google Scholar
  9. Askew, D., Ashmun, R., Simmons, B. & Cleveland, J. Constitutive c–myc expression in IL–3 dependent myeloid cell line suppresses cycle arrest and accelerates apoptosis. Oncogene 6, 1915–1922 (1991).
    CAS Google Scholar
  10. Shi, Y. et al. Role for c–myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257, 212–214 (1992).
    Article CAS Google Scholar
  11. Magrath, I., Jain, V. & Bhatia, K. Epstein-Barr virus and Burkitt's lymphoma. Sem. Cancer Biol. 3, 285–295 (1992).
    CAS Google Scholar
  12. Rabbitts, T.H., Hamlyn, R.H. & Baer, R. Altered nucleotide sequences of a translocated c–myc gene in Burkitt lymphoma. Nature 306, 760–765 (1983).
    Article CAS Google Scholar
  13. Rabbitts, T.H., Forster, A., Hamlyn, P. & Baer, R. Effect of somatic mutations within translocated c–myc genes in Burkitt lymphoma. Nature 309, 592–597 (1984).
    Article CAS Google Scholar
  14. Legouy, E. et al. Structure and expression of the murine L–myc gene. The EMBO J. 6, 3359–3366 (1987).
    Article CAS Google Scholar
  15. Gupta, S., Seth, A. & Davis, R.J. Transactivation of gene expression by Myc is inhibited by mutation at the phosphorylation sites Thr–58 and Ser–62. Proc. natn. Acad. Sci. U.S.A. 90, 3216–3220 (1993).
    Article CAS Google Scholar
  16. Gu, W., Cechova, K., Tassi, V. & Dalla-Favera, R. Opposite regulation of gene transcription and cell proliferation by c–Myc and Max. Proc. natn. Acad. Sci. U.S.A. 90, 2935–2939 (1993).
    Article CAS Google Scholar
  17. Seth, A., Alvarez, E., Gupta, S. & Davis, R.J. A phosphorylation site located in the NH2-terminal domain of c–Myc increases transactivation of gene expression. J. biol. Chem. 266, 23521–23524 (1991).
    CAS PubMed Google Scholar
  18. Potter, M. et al. Avian v–myc replaces chromosomal translocation in murine plasmacytomagenesis. Science 235, 787–789 (1987).
    Article CAS Google Scholar
  19. Cory, S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv. cancer Res. 47, 189–234 (1986).
    Article CAS Google Scholar
  20. Suen, T.-C. & Hung, M.-C. & Hung, M.-C. c–myc reverses neu-induced transformed morphology by transcriptional repression. Molec. cell. Biol. 11, 354–362 (1991).
    Article CAS Google Scholar

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Authors and Affiliations

  1. Pediatric Branch, Clinical Oncology Program, Building 10 Room 13N240, NCI/NIH, Bethesda, Maryland, 20892, USA
    K. Bhatia, G. Spangler, R. Iyer & I. Magrath
  2. Molecular Genetics Section, Laboratory of Genetics, NCI/NIH, Bethesda, Maryland, 20892, USA
    K. Huppi & D. Siwarski

Authors

  1. K. Bhatia
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  2. K. Huppi
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  3. G. Spangler
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  4. D. Siwarski
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  5. R. Iyer
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  6. I. Magrath
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Bhatia, K., Huppi, K., Spangler, G. et al. Point mutations in the c–Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas.Nat Genet 5, 56–61 (1993). https://doi.org/10.1038/ng0993-56

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