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. 1989 Jun;86(12):4589–4593. doi: 10.1073/pnas.86.12.4589

Growth- and tumor-promoting effects of deregulated BCL2 in human B-lymphoblastoid cells.

G Nunez 1, M Seto 1, S Seremetis 1, D Ferrero 1, F Grignani 1, S J Korsmeyer 1, R Dalla-Favera 1
PMCID: PMC287316  PMID: 2543982

Abstract

Human follicular B-cell lymphomas possess a t(14;18) that translocates a putative protooncogene, BCL2, into the immunoglobulin heavy chain locus. The normal BCL2 gene is quiescent in resting B cells, expressed in proliferating, but down-regulated in differentiated B cells. Inappropriately high levels of BCL2-immunoglobulin chimeric RNA are present in t(14;18) lymphomas for their mature B-cell stage. We examined the biologic effects of BCL2 deregulation in human B cells by introducing BCL2 into human B-lymphoblastoid cell lines (LCLs) with retroviral gene transfer. Although deregulated BCL2 expression as a single agent was not sufficient to confer tumorigenicity to LCLs, it consistently produced a 3- to 4-fold increment in LCL clonogenicity in soft agar. In addition, BCL2 deregulation complements the transforming effects of the MYC oncogene in LCLs. BCL2 augmented the clonogenicity of LCLs bearing exogenous MYC and increased the frequency and shortened the latency of tumor induction in immunodeficient mice. These results demonstrate a role for BCL2 as a protooncogene that affects B-cell growth and enhances B-cell neoplasia.

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Selected References

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

  1. Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
  2. Armentano D., Yu S. F., Kantoff P. W., von Ruden T., Anderson W. F., Gilboa E. Effect of internal viral sequences on the utility of retroviral vectors. J Virol. 1987 May;61(5):1647–1650. doi: 10.1128/jvi.61.5.1647-1650.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bakhshi A., Jensen J. P., Goldman P., Wright J. J., McBride O. W., Epstein A. L., Korsmeyer S. J. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. 1985 Jul;41(3):899–906. doi: 10.1016/s0092-8674(85)80070-2. [DOI] [PubMed] [Google Scholar]
  4. Bakhshi A., Wright J. J., Graninger W., Seto M., Owens J., Cossman J., Jensen J. P., Goldman P., Korsmeyer S. J. Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2396–2400. doi: 10.1073/pnas.84.8.2396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cleary M. L., Sklar J. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7439–7443. doi: 10.1073/pnas.82.21.7439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cleary M. L., Smith S. D., Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986 Oct 10;47(1):19–28. doi: 10.1016/0092-8674(86)90362-4. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. De Jong D., Voetdijk B. M., Beverstock G. C., van Ommen G. J., Willemze R., Kluin P. M. Activation of the c-myc oncogene in a precursor-B-cell blast crisis of follicular lymphoma, presenting as composite lymphoma. N Engl J Med. 1988 May 26;318(21):1373–1378. doi: 10.1056/NEJM198805263182106. [DOI] [PubMed] [Google Scholar]
  9. Gauwerky C. E., Haluska F. G., Tsujimoto Y., Nowell P. C., Croce C. M. Evolution of B-cell malignancy: pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8548–8552. doi: 10.1073/pnas.85.22.8548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Graninger W. B., Seto M., Boutain B., Goldman P., Korsmeyer S. J. Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Invest. 1987 Nov;80(5):1512–1515. doi: 10.1172/JCI113235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Leder A., Pattengale P. K., Kuo A., Stewart T. A., Leder P. Consequences of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasms and normal development. Cell. 1986 May 23;45(4):485–495. doi: 10.1016/0092-8674(86)90280-1. [DOI] [PubMed] [Google Scholar]
  12. Levine E. G., Arthur D. C., Frizzera G., Peterson B. A., Hurd D. D., Bloomfield C. D. There are differences in cytogenetic abnormalities among histologic subtypes of the non-Hodgkin's lymphomas. Blood. 1985 Dec;66(6):1414–1422. [PubMed] [Google Scholar]
  13. Lombardi L., Newcomb E. W., Dalla-Favera R. Pathogenesis of Burkitt lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected human B lymphoblasts. Cell. 1987 Apr 24;49(2):161–170. doi: 10.1016/0092-8674(87)90556-3. [DOI] [PubMed] [Google Scholar]
  14. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  15. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Miller A. D., Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986 Aug;6(8):2895–2902. doi: 10.1128/mcb.6.8.2895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Miller A. D., Trauber D. R., Buttimore C. Factors involved in production of helper virus-free retrovirus vectors. Somat Cell Mol Genet. 1986 Mar;12(2):175–183. doi: 10.1007/BF01560664. [DOI] [PubMed] [Google Scholar]
  18. Reed J. C., Cuddy M., Slabiak T., Croce C. M., Nowell P. C. Oncogenic potential of bcl-2 demonstrated by gene transfer. Nature. 1988 Nov 17;336(6196):259–261. doi: 10.1038/336259a0. [DOI] [PubMed] [Google Scholar]
  19. Reed J. C., Tsujimoto Y., Alpers J. D., Croce C. M., Nowell P. C. Regulation of bcl-2 proto-oncogene expression during normal human lymphocyte proliferation. Science. 1987 Jun 5;236(4806):1295–1299. doi: 10.1126/science.3495884. [DOI] [PubMed] [Google Scholar]
  20. Richardson M. E., Chen Q. G., Filippa D. A., Offit K., Hampton A., Koduru P. R., Jhanwar S. C., Lieberman P. H., Clarkson B. D., Chaganti R. S. Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes. Blood. 1987 Aug;70(2):444–447. [PubMed] [Google Scholar]
  21. Seremetis S., Inghirami G., Ferrero D., Lombardi L., Knowlest D. M., Dotto G. P., Dalla-Favera R. Different biological effects of c-myc and H-ras oncogene expression in EBV-infected human lymphoblasts. Curr Top Microbiol Immunol. 1988;141:290–297. doi: 10.1007/978-3-642-74006-0_39. [DOI] [PubMed] [Google Scholar]
  22. Seremetis S., Inghirami G., Ferrero D., Newcomb E. W., Knowles D. M., Dotto G. P., Dalla-Favera R. Transformation and plasmacytoid differentiation of EBV-infected human B lymphoblasts by ras oncogenes. Science. 1989 Feb 3;243(4891):660–663. doi: 10.1126/science.2536954. [DOI] [PubMed] [Google Scholar]
  23. Seto M., Jaeger U., Hockett R. D., Graninger W., Bennett S., Goldman P., Korsmeyer S. J. Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J. 1988 Jan;7(1):123–131. doi: 10.1002/j.1460-2075.1988.tb02791.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Tsujimoto Y., Gorham J., Cossman J., Jaffe E., Croce C. M. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science. 1985 Sep 27;229(4720):1390–1393. doi: 10.1126/science.3929382. [DOI] [PubMed] [Google Scholar]
  26. Tsujimoto Y., Ikegaki N., Croce C. M. Characterization of the protein product of bcl-2, the gene involved in human follicular lymphoma. Oncogene. 1987;2(1):3–7. [PubMed] [Google Scholar]
  27. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  28. 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]

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