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The Role of bcl-2 in Lymphoid Differentiation and Neoplastic Transformation

  • A. Strasser
  • A. W. Harris
  • S. Cory
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 182)

Abstract

Follicular lymphoma is one of the most common hematopoietic malignancies in the western world. Most (70–80%) of these tumors exhibit a characteristic t(14;18) chromosome translocation caused by recombination of the bcl-2 gene into the immunoglobulin (Ig) heavy chain locus [1–3]. The coding portion of bcl-2 remains unchanged but its regulation is presumably perturbed because of the influence of immunoglobulin regulatory sequences. The bcl-2 gene encodes a 26 kD non-glycosylated cytoplasmic protein [4, 5] which associates with membranes via its hydrophobic C-terminus [6]. It has been variously reported to be associated with the plasma membrane and perinuclear endoplasmic reticulum [5] and with the inner membrane of the mitochondrion [7]. The first clue to the unusual function of bcl-2 was the discovery that enforcing its expression in factor dependent cell lines enabled them to survive in the absence of growth factor [8]. This observation raised the possibility that the normal role of bcl-2 is to govern the life and death of lymphocytes during the generation and function of the immune system. Transgenic mice have been developed to test this hypothesis and to evaluate the oncogenic potential of bcl-2 [9–13].

Keywords

Follicular Lymphoma Immune Complex Glomerulonephritis Heavy Chain Locus Composite Lymphoma Lymphoid Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Tsujimoto Y, Finger LR, Yunis J, Nowell PC and Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226:1097–1099.PubMedCrossRefGoogle Scholar
  2. 2.
    Bakhshi A, Jensen JP, Goldman P, Wright J, McBride OW, Epstein AL and Korsmeyer SJ (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:899–906.PubMedCrossRefGoogle Scholar
  3. 3.
    Cleary ML, Smith SD and Sklar J (1986) Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47:19–28.PubMedCrossRefGoogle Scholar
  4. 4.
    Tsujimoto Y, Ikegaki N and Croce CM (1987) Characterization of the protein product of bcl-2, the gene involved in human follicular lymphoma. Oncogene 2:3–7.PubMedGoogle Scholar
  5. 5.
    Chen-Levy Z, Nourse J and Cleary ML (1989) The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. Mol Cell Biol 9:701–710.PubMedGoogle Scholar
  6. 6.
    Chen-Levy Z and Cleary ML (1990) Membrane topology of the Bcl-2 proto-oncogenic protein demonstrated in vitro. J Biol Chem 265:4929–4933.PubMedGoogle Scholar
  7. 7.
    Hockenbery D, Nunez G, Milliman C, Schreiber RD and Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336.PubMedCrossRefGoogle Scholar
  8. 8.
    Vaux DL, Cory S and Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442.PubMedCrossRefGoogle Scholar
  9. 9.
    McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP and Korsmeyer SJ (1989) bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57:79–88.PubMedCrossRefGoogle Scholar
  10. 10.
    Strasser A, Harris AW, Vaux DL, Webb E, Bath ML, Adams JM and Cory S (1990) Abnormalities of the immune system induced by dysregulated bcl-2 expression in transgenic mice. Curr Top Microbiol Immunol 166:175–181.PubMedCrossRefGoogle Scholar
  11. 11.
    Strasser A, Whittingham S, Vaux DL, Bath L, Adams JM, Cory S and Harris AW (1991) Enforced BCL-2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci. U S A 88:8661–8665.PubMedCrossRefGoogle Scholar
  12. 12.
    Strasser A, Harris AW and Cory S (1991) Bcl-2 transgene inhibits T cell death and perturbs thymic selfcensorship. Cell 67:889–899.PubMedCrossRefGoogle Scholar
  13. 13.
    Sentman CL, Shutter JR, Hockenbery D, Kanagawa O and Korsmeyer SJ (1991) bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67:879–888.PubMedCrossRefGoogle Scholar
  14. 14.
    McDonnell TJ, Nunez G, Platt FM, Hockenberry D, London L, McKearn JP and Korsmeyer SJ (1990) Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. Mol Cell Biol 10:1901–1907.PubMedGoogle Scholar
  15. 15.
    Nunez G, Hockenbery D, McDonnell TJ, Sorensen CM and Korsmeyer SJ (1991) Bcl-2 maintains B cell memory. Nature 353:71–73.PubMedCrossRefGoogle Scholar
  16. 16.
    Limpens J, de Jong D, van Krieken JHJM, Price GA, Young BD, van Ommen G-JB and Kluin PM (1991) Bcl-2/JH rearrrangements in benign lymphoid tissues with follicular hyperplasia. Oncogene 6:2271–2276.PubMedGoogle Scholar
  17. 17.
    Strasser A, Harris AW, Bath ML and Cory S (1990) Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348:331–333.PubMedCrossRefGoogle Scholar
  18. 18.
    Cumano A, Paige CJ, Iscove NN and Brady G (1992) Bipotential precursors of B cells and macrophages in murine fetal liver. Nature 356:612–615.PubMedCrossRefGoogle Scholar
  19. 19.
    de Jong D, Voetdijk MH, Beverstock GC, van Ommen GJB, Willemze R and Kluin PM (1988) Activation of the c-myc oncogene in a precursor-B-cell blast crisis of follicular lymphoma, presenting as composite lymphoma. New Eng J. Med. 318:1373–1378.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee JT, Innes DJ and Williams ME (1989) Sequential bcl-2 and c-myc oncogene rearrangements associated with the clinical transformation of non-Hodgkin’s lymphoma. J Clin Invest 84:1454–1459.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • A. Strasser
    • 1
  • A. W. Harris
    • 1
  • S. Cory
    • 1
  1. 1.The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne HospitalAustralia

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