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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1984 Nov;81(21):6798–6802. doi: 10.1073/pnas.81.21.6798

Activation of a translocated c-myc gene: role of structural alterations in the upstream region.

K G Wiman, B Clarkson, A C Hayday, H Saito, S Tonegawa, W S Hayward
PMCID: PMC392019  PMID: 6593728

Abstract

The translocated c-myc gene in AW-Ramos, a Burkitt lymphoma cell line carrying the 8;14 translocation, is expressed at 2- to 5-fold higher levels than c-myc in lymphoblastoid cell lines. The translocation event has joined c-myc to the IgM switch region. As a consequence, a recently identified immunoglobulin transcriptional enhancer element is not linked to the translocated c-myc gene. Chromosomal recombination occurs approximately equal to 340 nucleotides upstream of the c-myc 5' cap site, leaving all three c-myc exons intact. The nucleotide sequences of the two coding exons in the translocated c-myc gene are identical to those of the normal c-myc gene. Nucleotide sequence analyses of the first, noncoding c-myc exon and of the region between this exon and the chromosomal recombination point reveal two single-base differences from normal c-myc. Our data indicate that altered expression rather than an altered gene product is responsible for c-myc activation in AW-Ramos cells and that this is a result of either loss of regulatory sequences located greater than 340 nucleotides upstream of c-myc or disruption of normal c-myc regulation by one or both base substitutions. Alternatively, unidentified enhancer-like sequences in the Ig locus may alter the expression of c-myc.

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Selected References

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  1. Alitalo K., Schwab M., Lin C. C., Varmus H. E., Bishop J. M. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1707–1711. doi: 10.1073/pnas.80.6.1707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Battey J., Moulding C., Taub R., Murphy W., Stewart T., Potter H., Lenoir G., Leder P. The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell. 1983 Oct;34(3):779–787. doi: 10.1016/0092-8674(83)90534-2. [DOI] [PubMed] [Google Scholar]
  3. Bernard O., Cory S., Gerondakis S., Webb E., Adams J. M. Sequence of the murine and human cellular myc oncogenes and two modes of myc transcription resulting from chromosome translocation in B lymphoid tumours. EMBO J. 1983;2(12):2375–2383. doi: 10.1002/j.1460-2075.1983.tb01749.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernheim A., Berger R., Lenoir G. Cytogenetic studies on African Burkitt's lymphoma cell lines: t(8;14), t(2;8) and t(8;22) translocations. Cancer Genet Cytogenet. 1981 Jun;3(4):307–315. doi: 10.1016/0165-4608(81)90039-x. [DOI] [PubMed] [Google Scholar]
  5. Bishop J. M. Enemies within: the genesis of retrovirus oncogenes. Cell. 1981 Jan;23(1):5–6. doi: 10.1016/0092-8674(81)90263-4. [DOI] [PubMed] [Google Scholar]
  6. Campisi J., Gray H. E., Pardee A. B., Dean M., Sonenshein G. E. Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation. Cell. 1984 Feb;36(2):241–247. doi: 10.1016/0092-8674(84)90217-4. [DOI] [PubMed] [Google Scholar]
  7. Colby W. W., Chen E. Y., Smith D. H., Levinson A. D. Identification and nucleotide sequence of a human locus homologous to the v-myc oncogene of avian myelocytomatosis virus MC29. Nature. 1983 Feb 24;301(5902):722–725. doi: 10.1038/301722a0. [DOI] [PubMed] [Google Scholar]
  8. Collins S., Groudine M. Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line. Nature. 1982 Aug 12;298(5875):679–681. doi: 10.1038/298679a0. [DOI] [PubMed] [Google Scholar]
  9. Corden J., Wasylyk B., Buchwalder A., Sassone-Corsi P., Kedinger C., Chambon P. Promoter sequences of eukaryotic protein-coding genes. Science. 1980 Sep 19;209(4463):1406–1414. doi: 10.1126/science.6251548. [DOI] [PubMed] [Google Scholar]
  10. Dalla-Favera R., Bregni M., Erikson J., Patterson D., Gallo R. C., Croce C. M. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7824–7827. doi: 10.1073/pnas.79.24.7824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dalla-Favera R., Martinotti S., Gallo R. C., Erikson J., Croce C. M. Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science. 1983 Feb 25;219(4587):963–967. doi: 10.1126/science.6401867. [DOI] [PubMed] [Google Scholar]
  12. Dalla-Favera R., Wong-Staal F., Gallo R. C. Onc gene amplification in promyelocytic leukaemia cell line HL-60 and primary leukaemic cells of the same patient. Nature. 1982 Sep 2;299(5878):61–63. doi: 10.1038/299061a0. [DOI] [PubMed] [Google Scholar]
  13. Erikson J., ar-Rushdi A., Drwinga H. L., Nowell P. C., Croce C. M. Transcriptional activation of the translocated c-myc oncogene in burkitt lymphoma. Proc Natl Acad Sci U S A. 1983 Feb;80(3):820–824. doi: 10.1073/pnas.80.3.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fung Y. K., Crittenden L. B., Kung H. J. Orientation and position of avian leukosis virus DNA relative to the cellular oncogene c-myc in B-lymphoma tumors of highly susceptible 15I5 X 7(2) chickens. J Virol. 1982 Nov;44(2):742–746. doi: 10.1128/jvi.44.2.742-746.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gazin C., Dupont de Dinechin S., Hampe A., Masson J. M., Martin P., Stehelin D., Galibert F. Nucleotide sequence of the human c-myc locus: provocative open reading frame within the first exon. EMBO J. 1984 Feb;3(2):383–387. doi: 10.1002/j.1460-2075.1984.tb01816.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gelmann E. P., Psallidopoulos M. C., Papas T. S., Dalla-Favera R. Identification of reciprocal translocation sites within the c-myc oncogene and immunoglobulin mu locus in a Burkitt lymphoma. Nature. 1983 Dec 22;306(5945):799–803. doi: 10.1038/306799a0. [DOI] [PubMed] [Google Scholar]
  17. Grosveld F. G., Lund T., Murray E. J., Mellor A. L., Dahl H. H., Flavell R. A. The construction of cosmid libraries which can be used to transform eukaryotic cells. Nucleic Acids Res. 1982 Nov 11;10(21):6715–6732. doi: 10.1093/nar/10.21.6715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hamlyn P. H., Rabbitts T. H. Translocation joins c-myc and immunoglobulin gamma 1 genes in a Burkitt lymphoma revealing a third exon in the c-myc oncogene. Nature. 1983 Jul 14;304(5922):135–139. doi: 10.1038/304135a0. [DOI] [PubMed] [Google Scholar]
  19. Hayday A. C., Gillies S. D., Saito H., Wood C., Wiman K., Hayward W. S., Tonegawa S. Activation of a translocated human c-myc gene by an enhancer in the immunoglobulin heavy-chain locus. 1984 Jan 26-Feb 1Nature. 307(5949):334–340. doi: 10.1038/307334a0. [DOI] [PubMed] [Google Scholar]
  20. Hayward W. S., Neel B. G., Astrin S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature. 1981 Apr 9;290(5806):475–480. doi: 10.1038/290475a0. [DOI] [PubMed] [Google Scholar]
  21. Hsü K. J., He Q., McKenzie J. A., Weissert H., Perch-Nielsen K., Oberhänsli H., Kelts K., Labrecque J., Tauxe L., Krähenbühl U., Percival S. F., Jr, Wright R., Karpoff A. M., Petersen N., Tucker P., Poore R. Z., Gombos A. M., Pisciotto K., Carman M. F., Jr, Schreiber E. Mass mortality and its environmental and evolutionary consequences. Science. 1982 Apr 16;216(4543):249–256. doi: 10.1126/science.216.4543.249. [DOI] [PubMed] [Google Scholar]
  22. Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
  23. Kirsch I. R., Morton C. C., Nakahara K., Leder P. Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. Science. 1982 Apr 16;216(4543):301–303. doi: 10.1126/science.6801764. [DOI] [PubMed] [Google Scholar]
  24. Klein G., Giovanella B., Westman A., Stehlin J. S., Mumford D. An EBV-genome-negative cell line established from an American Burkitt lymphoma; receptor characteristics. EBV infectibility and permanent conversion into EBV-positive sublines by in vitro infection. Intervirology. 1975;5(6):319–334. doi: 10.1159/000149930. [DOI] [PubMed] [Google Scholar]
  25. Klein G. The role of gene dosage and genetic transpositions in carcinogenesis. Nature. 1981 Nov 26;294(5839):313–318. doi: 10.1038/294313a0. [DOI] [PubMed] [Google Scholar]
  26. Maguire R. T., Robins T. S., Thorgeirsson S. S., Heilman C. A. Expression of cellular myc and mos genes in undifferentiated B cell lymphomas of Burkitt and non-Burkitt types. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1947–1950. doi: 10.1073/pnas.80.7.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Malcolm S., Barton P., Murphy C., Ferguson-Smith M. A., Bentley D. L., Rabbitts T. H. Localization of human immunoglobulin kappa light chain variable region genes to the short arm of chromosome 2 by in situ hybridization. Proc Natl Acad Sci U S A. 1982 Aug;79(16):4957–4961. doi: 10.1073/pnas.79.16.4957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Marcu K. B., Harris L. J., Stanton L. W., Erikson J., Watt R., Croce C. M. Transcriptionally active c-myc oncogene is contained within NIARD, a DNA sequence associated with chromosome translocations in B-cell neoplasia. Proc Natl Acad Sci U S A. 1983 Jan;80(2):519–523. doi: 10.1073/pnas.80.2.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  30. McMaster G. K., Carmichael G. G. Analysis of single- and double-stranded nucleic acids on polyacrylamide and agarose gels by using glyoxal and acridine orange. Proc Natl Acad Sci U S A. 1977 Nov;74(11):4835–4838. doi: 10.1073/pnas.74.11.4835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Neel B. G., Jhanwar S. C., Chaganti R. S., Hayward W. S. Two human c-onc genes are located on the long arm of chromosome 8. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7842–7846. doi: 10.1073/pnas.79.24.7842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nishikori M., Hansen H., Jhanwar S., Fried J., Sordillo P., Koziner B., Lloyd K., Clarkson B. Establishment of a near-tetraploid B-cell lymphoma line with duplication of the 8;14 translocation. Cancer Genet Cytogenet. 1984 May;12(1):39–50. doi: 10.1016/0165-4608(84)90006-2. [DOI] [PubMed] [Google Scholar]
  33. Payne G. S., Bishop J. M., Varmus H. E. Multiple arrangements of viral DNA and an activated host oncogene in bursal lymphomas. Nature. 1982 Jan 21;295(5846):209–214. doi: 10.1038/295209a0. [DOI] [PubMed] [Google Scholar]
  34. Rabbitts T. H., Hamlyn P. H., Baer R. Altered nucleotide sequences of a translocated c-myc gene in Burkitt lymphoma. Nature. 1983 Dec 22;306(5945):760–765. doi: 10.1038/306760a0. [DOI] [PubMed] [Google Scholar]
  35. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  36. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  37. Saito H., Hayday A. C., Wiman K., Hayward W. S., Tonegawa S. Activation of the c-myc gene by translocation: a model for translational control. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7476–7480. doi: 10.1073/pnas.80.24.7476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shen-Ong G. L., Keath E. J., Piccoli S. P., Cole M. D. Novel myc oncogene RNA from abortive immunoglobulin-gene recombination in mouse plasmacytomas. Cell. 1982 Dec;31(2 Pt 1):443–452. doi: 10.1016/0092-8674(82)90137-4. [DOI] [PubMed] [Google Scholar]
  39. Siebenlist U., Hennighausen L., Battey J., Leder P. Chromatin structure and protein binding in the putative regulatory region of the c-myc gene in Burkitt lymphoma. Cell. 1984 Jun;37(2):381–391. doi: 10.1016/0092-8674(84)90368-4. [DOI] [PubMed] [Google Scholar]
  40. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  41. Stanton L. W., Watt R., Marcu K. B. Translocation, breakage and truncated transcripts of c-myc oncogene in murine plasmacytomas. Nature. 1983 Jun 2;303(5916):401–406. doi: 10.1038/303401a0. [DOI] [PubMed] [Google Scholar]
  42. Taub R., Kirsch I., Morton C., Lenoir G., Swan D., Tronick S., Aaronson S., Leder P. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7837–7841. doi: 10.1073/pnas.79.24.7837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Taub R., Moulding C., Battey J., Murphy W., Vasicek T., Lenoir G. M., Leder P. Activation and somatic mutation of the translocated c-myc gene in burkitt lymphoma cells. Cell. 1984 Feb;36(2):339–348. doi: 10.1016/0092-8674(84)90227-7. [DOI] [PubMed] [Google Scholar]
  44. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Watt R., Nishikura K., Sorrentino J., ar-Rushdi A., Croce C. M., Rovera G. The structure and nucleotide sequence of the 5' end of the human c-myc oncogene. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6307–6311. doi: 10.1073/pnas.80.20.6307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Westaway D., Payne G., Varmus H. E. Proviral deletions and oncogene base-substitutions in insertionally mutagenized c-myc alleles may contribute to the progression of avian bursal tumors. Proc Natl Acad Sci U S A. 1984 Feb;81(3):843–847. doi: 10.1073/pnas.81.3.843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yunis J. J. The chromosomal basis of human neoplasia. Science. 1983 Jul 15;221(4607):227–236. doi: 10.1126/science.6336310. [DOI] [PubMed] [Google Scholar]
  48. Zech L., Haglund U., Nilsson K., Klein G. Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Burkitt and non-Burkitt lymphomas. Int J Cancer. 1976 Jan 15;17(1):47–56. doi: 10.1002/ijc.2910170108. [DOI] [PubMed] [Google Scholar]
  49. ar-Rushdi A., Nishikura K., Erikson J., Watt R., Rovera G., Croce C. M. Differential expression of the translocated and the untranslocated c-myc oncogene in Burkitt lymphoma. Science. 1983 Oct 28;222(4622):390–393. doi: 10.1126/science.6414084. [DOI] [PubMed] [Google Scholar]

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