Abstract
Transgenic mice carrying either the c-myc or N-myc oncogene deregulated by the immunoglobulin heavy chain enhancer element (E mu) develop both pre-B and B cell lymphomas (E mu-c-myc and E mu-N-myc lymphomas). We report here that B cell lines derived from these tumors, as well as a line derived from v-myc retroviral transformation, simultaneously express surface immunoglobulin (a hallmark of mature B cells) as well as a common subset of genes normally restricted to the pre-B stage of development-including the recombinase activating genes RAG-1 and RAG-2. Continued RAG-1 and RAG-2 expression in these lines is associated with VDJ recombinase activity detected with a VDJ recombination substrate. Cross-linking of the surface immunoglobulin on these lines with an anti-mu antibody leads to rapid, specific and reversible down-regulation of RAG-1 and RAG-2 gene expression. We also find that a small but significant percentage of normal surface immunoglobulin bearing bone marrow B cells express the RAG-1 gene. These findings are discussed in the context of their possible implications for the control of specific gene expression during the pre-B to B cell transition.
Full text
PDFImages in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- Alt F. W., Blackwell T. K., Yancopoulos G. D. Development of the primary antibody repertoire. Science. 1987 Nov 20;238(4830):1079–1087. doi: 10.1126/science.3317825. [DOI] [PubMed] [Google Scholar]
- Alt F. W., Enea V., Bothwell A. L., Baltimore D. Activity of multiple light chain genes in murine myeloma cells producing a single, functional light chain. Cell. 1980 Aug;21(1):1–12. doi: 10.1016/0092-8674(80)90109-9. [DOI] [PubMed] [Google Scholar]
- Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
- Bender T. P., Kuehl W. M. Differential expression of the c-myb proto-oncogene marks the pre-B cell/B cell junction in murine B lymphoid tumors. J Immunol. 1987 Dec 1;139(11):3822–3827. [PubMed] [Google Scholar]
- Bender T. P., Kuehl W. M. Murine myb protooncogene mRNA: cDNA sequence and evidence for 5' heterogeneity. Proc Natl Acad Sci U S A. 1986 May;83(10):3204–3208. doi: 10.1073/pnas.83.10.3204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Birrer M. J., Segal S., DeGreve J. S., Kaye F., Sausville E. A., Minna J. D. L-myc cooperates with ras to transform primary rat embryo fibroblasts. Mol Cell Biol. 1988 Jun;8(6):2668–2673. doi: 10.1128/mcb.8.6.2668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blackwell T. K., Kretzner L., Blackwood E. M., Eisenman R. N., Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science. 1990 Nov 23;250(4984):1149–1151. doi: 10.1126/science.2251503. [DOI] [PubMed] [Google Scholar]
- Blackwell T. K., Moore M. W., Yancopoulos G. D., Suh H., Lutzker S., Selsing E., Alt F. W. Recombination between immunoglobulin variable region gene segments is enhanced by transcription. Nature. 1986 Dec 11;324(6097):585–589. doi: 10.1038/324585a0. [DOI] [PubMed] [Google Scholar]
- Boehm T., Gonzalez-Sarmiento R., Kennedy M., Rabbitts T. H. A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3927–3931. doi: 10.1073/pnas.88.9.3927. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chun J. J., Schatz D. G., Oettinger M. A., Jaenisch R., Baltimore D. The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system. Cell. 1991 Jan 11;64(1):189–200. doi: 10.1016/0092-8674(91)90220-s. [DOI] [PubMed] [Google Scholar]
- Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
- Cole M. D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. doi: 10.1146/annurev.ge.20.120186.002045. [DOI] [PubMed] [Google Scholar]
- Collum R. G., Alt F. W. Are myc proteins transcription factors? Cancer Cells. 1990 Mar;2(3):69–75. [PubMed] [Google Scholar]
- Coppola J. A., Cole M. D. Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment. Nature. 1986 Apr 24;320(6064):760–763. doi: 10.1038/320760a0. [DOI] [PubMed] [Google Scholar]
- Dildrop R., Ma A., Zimmerman K., Hsu E., Tesfaye A., DePinho R., Alt F. W. IgH enhancer-mediated deregulation of N-myc gene expression in transgenic mice: generation of lymphoid neoplasias that lack c-myc expression. EMBO J. 1989 Apr;8(4):1121–1128. doi: 10.1002/j.1460-2075.1989.tb03482.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dmitrovsky E., Kuehl W. M., Hollis G. F., Kirsch I. R., Bender T. P., Segal S. Expression of a transfected human c-myc oncogene inhibits differentiation of a mouse erythroleukaemia cell line. Nature. 1986 Aug 21;322(6081):748–750. doi: 10.1038/322748a0. [DOI] [PubMed] [Google Scholar]
- Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goodwin R. G., Friend D., Ziegler S. F., Jerzy R., Falk B. A., Gimpel S., Cosman D., Dower S. K., March C. J., Namen A. E. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell. 1990 Mar 23;60(6):941–951. doi: 10.1016/0092-8674(90)90342-c. [DOI] [PubMed] [Google Scholar]
- Hardy R. R., Carmack C. E., Shinton S. A., Kemp J. D., Hayakawa K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med. 1991 May 1;173(5):1213–1225. doi: 10.1084/jem.173.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jakobovits A., Schwab M., Bishop J. M., Martin G. R. Expression of N-myc in teratocarcinoma stem cells and mouse embryos. Nature. 1985 Nov 14;318(6042):188–191. doi: 10.1038/318188a0. [DOI] [PubMed] [Google Scholar]
- Kincade P. W., Lee G., Sun L., Watanabe T. Monoclonal rat antibodies to murine IgM determinants. J Immunol Methods. 1981;42(1):17–26. doi: 10.1016/0022-1759(81)90220-9. [DOI] [PubMed] [Google Scholar]
- Kleinfield R., Hardy R. R., Tarlinton D., Dangl J., Herzenberg L. A., Weigert M. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma. 1986 Aug 28-Sep 3Nature. 322(6082):843–846. doi: 10.1038/322843a0. [DOI] [PubMed] [Google Scholar]
- Kudo A., Melchers F. A second gene, VpreB in the lambda 5 locus of the mouse, which appears to be selectively expressed in pre-B lymphocytes. EMBO J. 1987 Aug;6(8):2267–2272. doi: 10.1002/j.1460-2075.1987.tb02500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
- Langdon W. Y., Harris A. W., Cory S., Adams J. M. The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell. 1986 Oct 10;47(1):11–18. doi: 10.1016/0092-8674(86)90361-2. [DOI] [PubMed] [Google Scholar]
- Leder P., Battey J., Lenoir G., Moulding C., Murphy W., Potter H., Stewart T., Taub R. Translocations among antibody genes in human cancer. Science. 1983 Nov 18;222(4625):765–771. doi: 10.1126/science.6356357. [DOI] [PubMed] [Google Scholar]
- Lieber M. R., Hesse J. E., Mizuuchi K., Gellert M. Developmental stage specificity of the lymphoid V(D)J recombination activity. Genes Dev. 1987 Oct;1(8):751–761. doi: 10.1101/gad.1.8.751. [DOI] [PubMed] [Google Scholar]
- Ma A., Smith R. K., Tesfaye A., Achacoso P., Dildrop R., Rosenberg N., Alt F. W. Mechanism of endogenous myc gene down-regulation in E mu-N-myc tumors. Mol Cell Biol. 1991 Jan;11(1):440–444. doi: 10.1128/mcb.11.1.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mushinski J. F., Davidson W. F., Morse H. C., 3rd Activation of cellular oncogenes in human and mouse leukemia-lymphomas: spontaneous and induced oncogene expression in murine B lymphocytic neoplasms. Cancer Invest. 1987;5(4):345–368. [PubMed] [Google Scholar]
- Möröy T., Fisher P., Guidos C., Ma A., Zimmerman K., Tesfaye A., DePinho R., Weissman I., Alt F. W. IgH enhancer deregulated expression of L-myc: abnormal T lymphocyte development and T cell lymphomagenesis. EMBO J. 1990 Nov;9(11):3659–3666. doi: 10.1002/j.1460-2075.1990.tb07577.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
- Rapp U. R., Cleveland J. L., Fredrickson T. N., Holmes K. L., Morse H. C., 3rd, Jansen H. W., Patschinsky T., Bister K. Rapid induction of hemopoietic neoplasms in newborn mice by a raf(mil)/myc recombinant murine retrovirus. J Virol. 1985 Jul;55(1):23–33. doi: 10.1128/jvi.55.1.23-33.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reitsma P. H., Rothberg P. G., Astrin S. M., Trial J., Bar-Shavit Z., Hall A., Teitelbaum S. L., Kahn A. J. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature. 1983 Dec 1;306(5942):492–494. doi: 10.1038/306492a0. [DOI] [PubMed] [Google Scholar]
- Rolink A., Melchers F. Molecular and cellular origins of B lymphocyte diversity. Cell. 1991 Sep 20;66(6):1081–1094. doi: 10.1016/0092-8674(91)90032-t. [DOI] [PubMed] [Google Scholar]
- Rosenbaum H., Webb E., Adams J. M., Cory S., Harris A. W. N-myc transgene promotes B lymphoid proliferation, elicits lymphomas and reveals cross-regulation with c-myc. EMBO J. 1989 Mar;8(3):749–755. doi: 10.1002/j.1460-2075.1989.tb03435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sakaguchi N., Melchers F. Lambda 5, a new light-chain-related locus selectively expressed in pre-B lymphocytes. Nature. 1986 Dec 11;324(6097):579–582. doi: 10.1038/324579a0. [DOI] [PubMed] [Google Scholar]
- Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
- Schwab M., Varmus H. E., Bishop J. M. Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture. Nature. 1985 Jul 11;316(6024):160–162. doi: 10.1038/316160a0. [DOI] [PubMed] [Google Scholar]
- Smith R. K., Zimmerman K., Yancopoulos G. D., Ma A., Alt F. W. Transcriptional down-regulation of N-myc expression during B-cell development. Mol Cell Biol. 1992 Apr;12(4):1578–1584. doi: 10.1128/mcb.12.4.1578. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thiele C. J., Israel M. A. Regulation of N-myc expression is a critical event controlling the ability of human neuroblasts to differentiate. Exp Cell Biol. 1988;56(6):321–333. doi: 10.1159/000163498. [DOI] [PubMed] [Google Scholar]
- Thiele C. J., Reynolds C. P., Israel M. A. Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. 1985 Jan 31-Feb 6Nature. 313(6001):404–406. doi: 10.1038/313404a0. [DOI] [PubMed] [Google Scholar]
- Turka L. A., Schatz D. G., Oettinger M. A., Chun J. J., Gorka C., Lee K., McCormack W. T., Thompson C. B. Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Science. 1991 Aug 16;253(5021):778–781. doi: 10.1126/science.1831564. [DOI] [PubMed] [Google Scholar]
- Vaux D. L., Adams J. M., Alexander W. S., Pike B. L. Immunologic competence of B cells subjected to constitutive c-myc oncogene expression in immunoglobulin heavy chain enhancer myc transgenic mice. J Immunol. 1987 Dec 1;139(11):3854–3860. [PubMed] [Google Scholar]
- Westin E. H., Wong-Staal F., Gelmann E. P., Dalla-Favera R., Papas T. S., Lautenberger J. A., Eva A., Reddy E. P., Tronick S. R., Aaronson S. A. Expression of cellular homologues of retroviral onc genes in human hematopoietic cells. Proc Natl Acad Sci U S A. 1982 Apr;79(8):2490–2494. doi: 10.1073/pnas.79.8.2490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weston K., Bishop J. M. Transcriptional activation by the v-myb oncogene and its cellular progenitor, c-myb. Cell. 1989 Jul 14;58(1):85–93. doi: 10.1016/0092-8674(89)90405-4. [DOI] [PubMed] [Google Scholar]
- Yancopoulos G. D., Desiderio S. V., Paskind M., Kearney J. F., Baltimore D., Alt F. W. Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature. 1984 Oct 25;311(5988):727–733. doi: 10.1038/311727a0. [DOI] [PubMed] [Google Scholar]
- Yancopoulos G. D., Nolan G. P., Pollock R., Prockop S., Li S. C., Herzenberg L. A., Alt F. W. A novel fluorescence-based system for assaying and separating live cells according to VDJ recombinase activity. Mol Cell Biol. 1990 Apr;10(4):1697–1704. doi: 10.1128/mcb.10.4.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yancopoulos G. D., Oltz E. M., Rathbun G., Berman J. E., Smith R. K., Lansford R. D., Rothman P., Okada A., Lee G., Morrow M. Isolation of coordinately regulated genes that are expressed in discrete stages of B-cell development. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5759–5763. doi: 10.1073/pnas.87.15.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yelton D. E., Desaymard C., Scharff M. D. Use of monoclonal anti-mouse immunoglobulin to detect mouse antibodies. Hybridoma. 1981;1(1):5–11. doi: 10.1089/hyb.1.1981.1.5. [DOI] [PubMed] [Google Scholar]
- Zimmerman K. A., Yancopoulos G. D., Collum R. G., Smith R. K., Kohl N. E., Denis K. A., Nau M. M., Witte O. N., Toran-Allerand D., Gee C. E. Differential expression of myc family genes during murine development. 1986 Feb 27-Mar 5Nature. 319(6056):780–783. doi: 10.1038/319780a0. [DOI] [PubMed] [Google Scholar]
- Zimmerman K., Alt F. W. Expression and function of myc family genes. Crit Rev Oncog. 1990;2(1):75–95. [PubMed] [Google Scholar]