Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1986 Dec 1;164(6):2049–2060. doi: 10.1084/jem.164.6.2049

Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis

PMCID: PMC2188476  PMID: 3491176

Abstract

AIDS (acquired immune deficiency syndrome) and ARC (AIDS-related complex) are associated with a spectrum of lymphoproliferative disorders ranging from lymphadenopathy syndrome (LAS), an apparently benign polyclonal lymphoid hyperplasia, to B cell non-Hodgkin's lymphoma (B-NHL), i.e., malignant, presumably monoclonal B cell proliferations. To gain insight into the process of lymphomagenesis in AIDS and to investigate a possible pathogenetic relationship between LAS and NHL, we investigated the clonality of the B or T lymphoid populations by Ig or T beta gene rearrangement analysis, the presence of rearrangements involving the c-myc oncogene locus, and the presence of human immunodeficiency virus (HIV) sequences in both LAS and B-NHL biopsies. Our data indicate that multiple clonal B cell expansions are present in a significant percentage of LAS (approximately 20%) and B- NHL (60%) biopsies. c-myc rearrangements/translocations are detectable in 9 of our 10 NHLs, but not in any of the LAS cases. However, only one of the B cell clones, identified by Ig gene rearrangements carries a c- myc gene rearrangement, suggesting that only one clone carries the genetic abnormality associated with malignant B cell lymphoma. Furthermore, the frequency of detection of c-myc rearrangements in AIDS- associated NHLs of both Burkitt and non-Burkitt type suggest that the biological alterations present in AIDS favor the development of lymphomas carrying activated c-myc oncogenes. Finally, our data show that HIV DNA sequences are not detectable in LAS nor in NHL B cell clones, suggesting that HIV does not play a direct role in NHL development. Taken together, these observations suggest a model of multistep lymphomagenesis in AIDS in which LAS would represent a predisposing condition to NHL. Immunosuppression and EBV infection present in LAS can favor the expansion of B cell clones, which in turn may increase the probability of occurrence of c-myc rearrangements leading to malignant transformation.

Full Text

The Full Text of this article is available as a PDF (961.9 KB).

Selected References

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

  1. Centers for Disease Control (CDC) Revision of the case definition of acquired immunodeficiency syndrome for national reporting--United States. MMWR Morb Mortal Wkly Rep. 1985 Jun 28;34(25):373–375. [PubMed] [Google Scholar]
  2. Chaganti R. S., Jhanwar S. C., Koziner B., Arlin Z., Mertelsmann R., Clarkson B. D. Specific translocations characterize Burkitt's-like lymphoma of homosexual men with the acquired immunodeficiency syndrome. Blood. 1983 Jun;61(6):1265–1268. [PubMed] [Google Scholar]
  3. Cleary M. L., Sklar J. Lymphoproliferative disorders in cardiac transplant recipients are multiclonal lymphomas. Lancet. 1984 Sep 1;2(8401):489–493. doi: 10.1016/s0140-6736(84)92566-2. [DOI] [PubMed] [Google Scholar]
  4. Cleary M. L., Warnke R., Sklar J. Monoclonality of lymphoproliferative lesions in cardiac-transplant recipients. Clonal analysis based on immunoglobulin-gene rearrangements. N Engl J Med. 1984 Feb 23;310(8):477–482. doi: 10.1056/NEJM198402233100801. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  7. Davis M., Malcolm S., Rabbitts T. H. Chromosome translocation can occur on either side of the c-myc oncogene in Burkitt lymphoma cells. Nature. 1984 Mar 15;308(5956):286–288. doi: 10.1038/308286a0. [DOI] [PubMed] [Google Scholar]
  8. Doll D. C., List A. F. Burkitt's lymphoma in a homosexual. Lancet. 1982 May 1;1(8279):1026–1027. doi: 10.1016/s0140-6736(82)92031-1. [DOI] [PubMed] [Google Scholar]
  9. Flug F., Pelicci P. G., Bonetti F., Knowles D. M., 2nd, Dalla-Favera R. T-cell receptor gene rearrangements as markers of lineage and clonality in T-cell neoplasms. Proc Natl Acad Sci U S A. 1985 May;82(10):3460–3464. doi: 10.1073/pnas.82.10.3460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Knowles D. M., 2nd, Pelicci P. G., Dalla-Favera R. T-cell receptor beta chain gene rearrangements: genetic markers of T-cell lineage and clonality. Hum Pathol. 1986 Jun;17(6):546–551. doi: 10.1016/s0046-8177(86)80125-3. [DOI] [PubMed] [Google Scholar]
  11. Knowles D. M., 2nd, Tolidjian B., Marboe C. C., Mittler R. S., Talle M. A., Goldstein G. Distribution of antigens defined by OKB monoclonal antibodies on benign and malignant lymphoid cells and on nonlymphoid tissues. Blood. 1984 Apr;63(4):886–896. [PubMed] [Google Scholar]
  12. Konttinen Y. T., Bluestein H. G., Zvaifler N. J. Regulation of the growth of Epstein-Barr virus-infected B cells. I. Growth regression by E rosetting cells from VCA-positive donors is a combined effect of autologous mixed leukocyte reaction and activation of T8+ memory cells. J Immunol. 1985 Apr;134(4):2287–2293. [PubMed] [Google Scholar]
  13. Korsmeyer S. J., Hieter P. A., Ravetch J. V., Poplack D. G., Waldmann T. A., Leder P. Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7096–7100. doi: 10.1073/pnas.78.11.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Luciw P. A., Potter S. J., Steimer K., Dina D., Levy J. A. Molecular cloning of AIDS-associated retrovirus. Nature. 1984 Dec 20;312(5996):760–763. doi: 10.1038/312760a0. [DOI] [PubMed] [Google Scholar]
  15. Pelicci P. G., Knowles D. M., 2nd, Magrath I., Dalla-Favera R. Chromosomal breakpoints and structural alterations of the c-myc locus differ in endemic and sporadic forms of Burkitt lymphoma. Proc Natl Acad Sci U S A. 1986 May;83(9):2984–2988. doi: 10.1073/pnas.83.9.2984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Petersen J. M., Tubbs R. R., Savage R. A., Calabrese L. C., Proffitt M. R., Manolova Y., Manolov G., Shumaker A., Tatsumi E., McClain K. Small noncleaved B cell Burkitt-like lymphoma with chromosome t(8;14) translocation and Epstein-Barr virus nuclear-associated antigen in a homosexual man with acquired immune deficiency syndrome. Am J Med. 1985 Jan;78(1):141–148. doi: 10.1016/0002-9343(85)90475-9. [DOI] [PubMed] [Google Scholar]
  17. Rutgers J. L., Wieczorek R., Bonetti F., Kaplan K. L., Posnett D. N., Friedman-Kien A. E., Knowles D. M., 2nd The expression of endothelial cell surface antigens by AIDS-associated Kaposi's sarcoma. Evidence for a vascular endothelial cell origin. Am J Pathol. 1986 Mar;122(3):493–499. [PMC free article] [PubMed] [Google Scholar]
  18. Saxinger W. C., Levine P. H., Dean A. G., de Thé G., Lange-Wantzin G., Moghissi J., Laurent F., Hoh M., Sarngadharan M. G., Gallo R. C. Evidence for exposure to HTLV-III in Uganda before 1973. Science. 1985 Mar 1;227(4690):1036–1038. doi: 10.1126/science.2983417. [DOI] [PubMed] [Google Scholar]
  19. Shibuya A., Saitoh K., Tsuneyoshi H., Tanaka S. Burkitt's lymphoma in a haemophiliac. Lancet. 1983 Dec 17;2(8364):1432–1432. doi: 10.1016/s0140-6736(83)90970-4. [DOI] [PubMed] [Google Scholar]
  20. Sklar J., Cleary M. L., Thielemans K., Gralow J., Warnke R., Levy R. Biclonal B-cell lymphoma. N Engl J Med. 1984 Jul 5;311(1):20–27. doi: 10.1056/NEJM198407053110104. [DOI] [PubMed] [Google Scholar]
  21. Spector B. D., Perry G. S., 3rd, Kersey J. H. Genetically determined immunodeficiency diseases (GDID) and malignancy: report from the immunodeficiency--cancer registry. Clin Immunol Immunopathol. 1978 Sep;11(1):12–29. doi: 10.1016/0090-1229(78)90200-3. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Toyonaga B., Yanagi Y., Suciu-Foca N., Minden M., Mak T. W. Rearrangements of T-cell receptor gene YT35 in human DNA from thymic leukaemia T-cell lines and functional T-cell clones. 1984 Sep 27-Oct 3Nature. 311(5984):385–387. doi: 10.1038/311385a0. [DOI] [PubMed] [Google Scholar]
  24. Whang-Peng J., Lee E. C., Sieverts H., Magrath I. T. Burkitt's lymphoma in AIDS: cytogenetic study. Blood. 1984 Apr;63(4):818–822. [PubMed] [Google Scholar]
  25. Ziegler J. L., Beckstead J. A., Volberding P. A., Abrams D. I., Levine A. M., Lukes R. J., Gill P. S., Burkes R. L., Meyer P. R., Metroka C. E. Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med. 1984 Aug 30;311(9):565–570. doi: 10.1056/NEJM198408303110904. [DOI] [PubMed] [Google Scholar]
  26. de-Thé G., Geser A., Day N. E., Tukei P. M., Williams E. H., Beri D. P., Smith P. G., Dean A. G., Bronkamm G. W., Feorino P. Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt's lymphoma from Ugandan prospective study. Nature. 1978 Aug 24;274(5673):756–761. doi: 10.1038/274756a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES