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. 1992 Oct;141(4):949–953.

Proto-oncogene analysis in multiple myeloma.

M Ladanyi 1, S Wang 1, R Niesvizky 1, H Feiner 1, J Michaeli 1
PMCID: PMC1886641  PMID: 1415486

Abstract

The genetic basis for the development of multiple myeloma (MM) remains poorly understood, in part because MM has thus far been relatively refractory to cytogenetic analysis. The few cases karyotyped have pointed to involvement of 11q13, site of the BCL1 proto-oncogene, or of 8q24, site of the MYC proto-oncogene. A recent molecular study detected rearrangements distal to the MYC gene in 16% of MM, using the MLVI-4 probe. The immunocytochemical demonstration of BCL2 protein overexpression in at least some cases of MM has suggested the possibility of translocation-mediated deregulation of the BCL2 proto-oncogene. The configuration of the BCL2 gene in MM, however, has not yet been defined using all available breakpoint probes. To address these issues, we studied 17 patients with plasma cell dyscrasias (16 MM, 1 plasmacytoma) by Southern blotting using the major breakpoint region (MBR), minor cluster region (MCR), and 5' cDNA (pB16) BCL2 breakpoint probes; with the BCL1 major translocation cluster (MTC) breakpoint probe; and with a probe to the MYC-associated MLVI-4 region (PA1.3SB). In all 17 cases, rearrangement of one or both alleles of the immunoglobulin heavy chain gene had been demonstrated, thereby confirming the presence of tumor DNA in the samples studied. None of the cases tested showed a rearrangement with the MBR BCL2 (0/16), MCR BCL2 (0/17), 5' cDNA BCL2 (0/16), BCL1 MTC (0/15), or MLVI-4 (0/15) probes. These results suggest that if BCL2 deregulation does indeed occur in MM, a mechanism other than translocation must be involved in most cases. Furthermore, rearrangements distal to the MYC gene, in the region of the MLVI-4 probe, may be less common than previously thought. Finally, a significant proportion of translocation breakpoints in band 11q13 may not be detected by the BCL1 MTC probe in MM, as is true in lymphomas.

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Selected References

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

  1. Adachi M., Tefferi A., Greipp P. R., Kipps T. J., Tsujimoto Y. Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med. 1990 Feb 1;171(2):559–564. doi: 10.1084/jem.171.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bakkus M. H., Brakel-van Peer K. M., Michiels J. J., van 't Veer M. B., Benner R. Amplification of the c-myc and the pvt-like region in human multiple myeloma. Oncogene. 1990 Sep;5(9):1359–1364. [PubMed] [Google Scholar]
  3. Bergsagel D. E. Plasma cell myeloma: biology and treatment. Annu Rev Med. 1991;42:167–178. doi: 10.1146/annurev.me.42.020191.001123. [DOI] [PubMed] [Google Scholar]
  4. Cleary M. L., Galili N., Sklar J. Detection of a second t(14;18) breakpoint cluster region in human follicular lymphomas. J Exp Med. 1986 Jul 1;164(1):315–320. doi: 10.1084/jem.164.1.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Dewald G. W., Kyle R. A., Hicks G. A., Greipp P. R. The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood. 1985 Aug;66(2):380–390. [PubMed] [Google Scholar]
  7. Fourney R., Palmer M., Ng A., Dietrich K., Belch A., Paterson M., Brox L. Elevated c-myc messenger RNA in multiple myeloma cell lines. Dis Markers. 1990 May-Jun;8(3):117–124. [PubMed] [Google Scholar]
  8. Gould J., Alexanian R., Goodacre A., Pathak S., Hecht B., Barlogie B. Plasma cell karyotype in multiple myeloma. Blood. 1988 Feb;71(2):453–456. [PubMed] [Google Scholar]
  9. Hamilton M. S., Barker H. F., Ball J., Drew M., Abbot S. D., Franklin I. M. Normal and neoplastic human plasma cells express bcl-2 antigen. Leukemia. 1991 Sep;5(9):768–771. [PubMed] [Google Scholar]
  10. Koduru P. R., Offit K., Filippa D. A. Molecular analysis of breaks in BCL-1 proto-oncogene in B-cell lymphomas with abnormalities of 11q13. Oncogene. 1989 Jul;4(7):929–934. [PubMed] [Google Scholar]
  11. Lisse I. M., Drivsholm A., Christoffersen P. Occurrence and type of chromosomal abnormalities in consecutive malignant monoclonal gammopathies: correlation with survival. Cancer Genet Cytogenet. 1988 Oct 1;35(1):27–36. doi: 10.1016/0165-4608(88)90117-3. [DOI] [PubMed] [Google Scholar]
  12. McKeithan T. W. Molecular biology of non-Hodgkin's lymphomas. Semin Oncol. 1990 Feb;17(1):30–42. [PubMed] [Google Scholar]
  13. Neri A., Murphy J. P., Cro L., Ferrero D., Tarella C., Baldini L., Dalla-Favera R. Ras oncogene mutation in multiple myeloma. J Exp Med. 1989 Nov 1;170(5):1715–1725. doi: 10.1084/jem.170.5.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ngan B. Y., Chen-Levy Z., Weiss L. M., Warnke R. A., Cleary M. L. Expression in non-Hodgkin's lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. N Engl J Med. 1988 Jun 23;318(25):1638–1644. doi: 10.1056/NEJM198806233182502. [DOI] [PubMed] [Google Scholar]
  15. Nishida K., Taniwaki M., Misawa S., Abe T. Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Res. 1989 Mar 1;49(5):1275–1281. [PubMed] [Google Scholar]
  16. Nobuyoshi M., Kawano M., Tanaka H., Ishikawa H., Tanabe O., Iwato K., Asaoku H., Sakai A., Kuramoto A. Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells. Br J Haematol. 1991 Apr;77(4):523–528. doi: 10.1111/j.1365-2141.1991.tb08620.x. [DOI] [PubMed] [Google Scholar]
  17. Palumbo A. P., Boccadoro M., Battaglio S., Corradini P., Tsichlis P. N., Huebner K., Pileri A., Croce C. M. Human homologue of Moloney leukemia virus integration-4 locus (MLVI-4), located 20 kilobases 3' of the myc gene, is rearranged in multiple myelomas. Cancer Res. 1990 Oct 15;50(20):6478–6482. [PubMed] [Google Scholar]
  18. Palumbo A. P., Pileri A., Dianzani U., Massaia M., Boccadoro M., Calabretta B. Altered expression of growth-regulated protooncogenes in human malignant plasma cells. Cancer Res. 1989 Sep 1;49(17):4701–4704. [PubMed] [Google Scholar]
  19. Paquette R. L., Berenson J., Lichtenstein A., McCormick F., Koeffler H. P. Oncogenes in multiple myeloma: point mutation of N-ras. Oncogene. 1990 Nov;5(11):1659–1663. [PubMed] [Google Scholar]
  20. Pezzella F., Tse A. G., Cordell J. L., Pulford K. A., Gatter K. C., Mason D. Y. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed] [Google Scholar]
  21. Raffeld M., Jaffe E. S. bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood. 1991 Jul 15;78(2):259–263. [PubMed] [Google Scholar]
  22. Raghoebier S., van Krieken J. H., Kluin-Nelemans J. C., Gillis A., van Ommen G. J., Ginsberg A. M., Raffeld M., Kluin P. M. Oncogene rearrangements in chronic B-cell leukemia. Blood. 1991 Apr 1;77(7):1560–1564. [PubMed] [Google Scholar]
  23. 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]
  24. Rosenberg C. L., Wong E., Petty E. M., Bale A. E., Tsujimoto Y., Harris N. L., Arnold A. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9638–9642. doi: 10.1073/pnas.88.21.9638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Selvanayagam P., Blick M., Narni F., van Tuinen P., Ledbetter D. H., Alexanian R., Saunders G. F., Barlogie B. Alteration and abnormal expression of the c-myc oncogene in human multiple myeloma. Blood. 1988 Jan;71(1):30–35. [PubMed] [Google Scholar]
  26. Tsujimoto Y., Bashir M. M., Givol I., Cossman J., Jaffe E., Croce C. M. DNA rearrangements in human follicular lymphoma can involve the 5' or the 3' region of the bcl-2 gene. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1329–1331. doi: 10.1073/pnas.84.5.1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tsujimoto Y., Jaffe E., Cossman J., Gorham J., Nowell P. C., Croce C. M. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature. 1985 May 23;315(6017):340–343. doi: 10.1038/315340a0. [DOI] [PubMed] [Google Scholar]
  28. Vandenberghe E., De Wolf-Peeters C., van den Oord J., Wlodarska I., Delabie J., Stul M., Thomas J., Michaux J. L., Mecucci C., Cassiman J. J. Translocation (11;14): a cytogenetic anomaly associated with B-cell lymphomas of non-follicle centre cell lineage. J Pathol. 1991 Jan;163(1):13–18. doi: 10.1002/path.1711630104. [DOI] [PubMed] [Google Scholar]
  29. Weiss L. M., Warnke R. A., Sklar J., Cleary M. L. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med. 1987 Nov 5;317(19):1185–1189. doi: 10.1056/NEJM198711053171904. [DOI] [PubMed] [Google Scholar]
  30. Williams M. E., Meeker T. C., Swerdlow S. H. Rearrangement of the chromosome 11 bcl-1 locus in centrocytic lymphoma: analysis with multiple breakpoint probes. Blood. 1991 Jul 15;78(2):493–498. [PubMed] [Google Scholar]
  31. Withers D. A., Harvey R. C., Faust J. B., Melnyk O., Carey K., Meeker T. C. Characterization of a candidate bcl-1 gene. Mol Cell Biol. 1991 Oct;11(10):4846–4853. doi: 10.1128/mcb.11.10.4846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zutter M., Hockenbery D., Silverman G. A., Korsmeyer S. J. Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. Blood. 1991 Aug 15;78(4):1062–1068. [PubMed] [Google Scholar]

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