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. 1995 Dec 19;92(26):12520–12524. doi: 10.1073/pnas.92.26.12520

Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.

A Migliazza 1, S Martinotti 1, W Chen 1, C Fusco 1, B H Ye 1, D M Knowles 1, K Offit 1, R S Chaganti 1, R Dalla-Favera 1
PMCID: PMC40389  PMID: 8618933

Abstract

The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL). We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BLC6 alleles indicating their independence from chromosomal rearrangements and linkage to immunoglobulin genes. These alterations identify a mechanism of genetic instability in malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression.

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Selected References

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

  1. Albagli O., Dhordain P., Deweindt C., Lecocq G., Leprince D. The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins. Cell Growth Differ. 1995 Sep;6(9):1193–1198. [PubMed] [Google Scholar]
  2. Bastard C., Deweindt C., Kerckaert J. P., Lenormand B., Rossi A., Pezzella F., Fruchart C., Duval C., Monconduit M., Tilly H. LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. Blood. 1994 May 1;83(9):2423–2427. [PubMed] [Google Scholar]
  3. Betz A. G., Neuberger M. S., Milstein C. Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today. 1993 Aug;14(8):405–411. doi: 10.1016/0167-5699(93)90144-a. [DOI] [PubMed] [Google Scholar]
  4. Cattoretti G., Chang C. C., Cechova K., Zhang J., Ye B. H., Falini B., Louie D. C., Offit K., Chaganti R. S., Dalla-Favera R. BCL-6 protein is expressed in germinal-center B cells. Blood. 1995 Jul 1;86(1):45–53. [PubMed] [Google Scholar]
  5. Dalla-Favera R., Ye B. H., Lo Coco F., Chang C. C., Cechova K., Zhang J., Migliazza A., Mellado W., Niu H., Chaganti S. BCL-6 and the molecular pathogenesis of B-cell lymphoma. Cold Spring Harb Symp Quant Biol. 1994;59:117–123. doi: 10.1101/sqb.1994.059.01.015. [DOI] [PubMed] [Google Scholar]
  6. Gaidano G., Hauptschein R. S., Parsa N. Z., Offit K., Rao P. H., Lenoir G., Knowles D. M., Chaganti R. S., Dalla-Favera R. Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma. Blood. 1992 Oct 1;80(7):1781–1787. [PubMed] [Google Scholar]
  7. Ikematsu H., Harindranath N., Ueki Y., Notkins A. L., Casali P. Clonal analysis of a human antibody response. II. Sequences of the VH genes of human IgM, IgG, and IgA to rabies virus reveal preferential utilization of VHIII segments and somatic hypermutation. J Immunol. 1993 Feb 15;150(4):1325–1337. [PMC free article] [PubMed] [Google Scholar]
  8. Ikematsu H., Kasaian M. T., Schettino E. W., Casali P. Structural analysis of the VH-D-JH segments of human polyreactive IgG mAb. Evidence for somatic selection. J Immunol. 1993 Oct 1;151(7):3604–3616. [PMC free article] [PubMed] [Google Scholar]
  9. Kerckaert J. P., Deweindt C., Tilly H., Quief S., Lecocq G., Bastard C. LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat Genet. 1993 Sep;5(1):66–70. doi: 10.1038/ng0993-66. [DOI] [PubMed] [Google Scholar]
  10. Kim S., Davis M., Sinn E., Patten P., Hood L. Antibody diversity: somatic hypermutation of rearranged VH genes. Cell. 1981 Dec;27(3 Pt 2):573–581. doi: 10.1016/0092-8674(81)90399-8. [DOI] [PubMed] [Google Scholar]
  11. Kocks C., Rajewsky K. Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol. 1989;7:537–559. doi: 10.1146/annurev.iy.07.040189.002541. [DOI] [PubMed] [Google Scholar]
  12. Küppers R., Zhao M., Hansmann M. L., Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 1993 Dec 15;12(13):4955–4967. doi: 10.1002/j.1460-2075.1993.tb06189.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lo Coco F., Ye B. H., Lista F., Corradini P., Offit K., Knowles D. M., Chaganti R. S., Dalla-Favera R. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. Blood. 1994 Apr 1;83(7):1757–1759. [PubMed] [Google Scholar]
  14. Loeb L. A. Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res. 1994 Oct 1;54(19):5059–5063. [PubMed] [Google Scholar]
  15. MacLennan I. C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  16. Menezes J., Leibold W., Klein G., Clements G. Establishment and characterization of an Epstein-Barr virus (EBC)-negative lymphoblastoid B cell line (BJA-B) from an exceptional, EBV-genome-negative African Burkitt's lymphoma. Biomedicine. 1975 Jul;22(4):276–284. [PubMed] [Google Scholar]
  17. Miki T., Kawamata N., Hirosawa S., Aoki N. Gene involved in the 3q27 translocation associated with B-cell lymphoma, BCL5, encodes a Krüppel-like zinc-finger protein. Blood. 1994 Jan 1;83(1):26–32. [PubMed] [Google Scholar]
  18. Neri A., Knowles D. M., Greco A., McCormick F., Dalla-Favera R. Analysis of RAS oncogene mutations in human lymphoid malignancies. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9268–9272. doi: 10.1073/pnas.85.23.9268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Offit K., Lo Coco F., Louie D. C., Parsa N. Z., Leung D., Portlock C., Ye B. H., Lista F., Filippa D. A., Rosenbaum A. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med. 1994 Jul 14;331(2):74–80. doi: 10.1056/NEJM199407143310202. [DOI] [PubMed] [Google Scholar]
  20. Otsuki T., Yano T., Clark H. M., Bastard C., Kerckaert J. P., Jaffe E. S., Raffeld M. Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkin's lymphomas: results of rearrangement and gene expression studies and a mutational analysis of coding region sequences. Blood. 1995 May 15;85(10):2877–2884. [PubMed] [Google Scholar]
  21. Rabbitts T. H., Hamlyn P. H., Baer R. Altered nucleotide sequences of a translocated c-myc gene in Burkitt lymphoma. Nature. 1983 Dec 22;306(5945):760–765. doi: 10.1038/306760a0. [DOI] [PubMed] [Google Scholar]
  22. Tanaka S., Louie D. C., Kant J. A., Reed J. C. Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. Blood. 1992 Jan 1;79(1):229–237. [PubMed] [Google Scholar]
  23. Tweeddale M. E., Lim B., Jamal N., Robinson J., Zalcberg J., Lockwood G., Minden M. D., Messner H. A. The presence of clonogenic cells in high-grade malignant lymphoma: a prognostic factor. Blood. 1987 May;69(5):1307–1314. [PubMed] [Google Scholar]
  24. Ye B. H., Rao P. H., Chaganti R. S., Dalla-Favera R. Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res. 1993 Jun 15;53(12):2732–2735. [PubMed] [Google Scholar]
  25. Yélamos J., Klix N., Goyenechea B., Lozano F., Chui Y. L., González Fernández A., Pannell R., Neuberger M. S., Milstein C. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature. 1995 Jul 20;376(6537):225–229. doi: 10.1038/376225a0. [DOI] [PubMed] [Google Scholar]

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