Abstract
The BCL6 gene, which functions as a transcription repressor, is the target of multiple chromosomal translocations in non-Hodgkin's lymphomas (NHL). These translocations occur in the nontranslated region of the BCL6 gene, juxtaposing regulatory sequences of the diverse partner genes to the open reading frame of the BCL6 gene and thus are thought to deregulate BCL6 gene expression. The levels of expression of the BCL6 gene and protein have been demonstrated to predict the clinical outcome of diffuse large B-cell lymphomas. By contrast, the prognostic significance of BCL6 gene translocations is unclear. In this study we have sought an explanation for this apparent discrepancy. We examined tumors with a variety of different BCL6 translocations and therefore with a variety of potentially substituted promoters. We found no increase in total BCL6 mRNA levels in the NHL specimens harboring BCL6 gene translocation. Indeed, some of these tumors expressed relatively low quantities of the BCL6 mRNA. We also sought to determine whether BCL6 transcription occurs from the rearranged or from the normal untranslocated allele in these tumors. We demonstrate that lymphoma cell lines and majority of NHL tumor specimens expressed BCL6 mRNA predominantly from the rearranged allele that may come under the control of various partner gene promoters. However, few NHL tumors with BCL6 gene translocations expressed BCL6 mRNA equally from the rearranged and the nonrearranged alleles. Neither the nature of the substituted promoters nor the presence of activating mutations in the BCL6 regulatory sequences correlated with the allelic expression of the BCL6 gene in these tumors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large- cell lymphoma. Science 1993; 262: 747–750.
Seyfert VL, Allman D, He Y, Staudt LM . Transcriptional repression by the proto-oncogene BCL-6. Oncogene 1996; 12: 2331–2342.
Kerckaert JP, 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; 5: 66–70.
Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B et al. BCL-6 protein is expressed in germinal-center B cells. Blood 1995; 86: 45–53.
Onizuka T, Moriyama M, Yamochi T, Kuroda T, Kazama A, Kanazawa N et al. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood 1995; 86: 28–37.
Falini B, Fizzotti M, Pileri S, Liso A, Pasqualucci L, Flenghi L . Bcl-6 protein expression in normal and neoplastic lymphoid tissues. Ann Oncol 1997; 8: 101–104.
Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2- type inflammation. Nat Genet 1997; 16: 161–170.
Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM . Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997; 276: 589–592.
Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F et al. LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. Blood 1994; 83: 2423–2427.
Otsuki T, Yano T, Clark HM, Bastard C, Kerckaert JP, Jaffe ES et al. 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; 85: 2877–2884.
Lo Coco F, Ye BH, Lista F, Corradini P, Offit K, Knowles DM et al. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. Blood 1994; 83: 1757–1759.
Akasaka H, Akasaka T, Kurata M, Ueda C, Shimizu A, Uchiyama T et al. Molecular anatomy of BCL6 translocations revealed by long-distance polymerase chain reaction-based assays. Cancer Res 2000; 60: 2335–2341.
Lossos IS, Jacobs Y, Cleary ML, Levy R, Re: Akasaka H et al. Molecular anatomy of BCL6 translocations revealed by long-distance polymerase chain reaction-based assays. Cancer Res 2000; 60: 2335–2341, Cancer Res 2001; 61: 7363–7364.
Wlodarska I, Mecucci C, Stul M, Michaux L, Pittaluga S, Hernandez JM et al. Fluorescence in situ hybridization identifies new chromosomal changes involving 3q27 in non-Hodgkin's lymphomas with BCL6/LAZ3 rearrangement. Genes Chromosomes Cancer 1995; 14: 1–7.
Ohno H, Fukuhara S . Significance of rearrangement of the BCL6 gene in B-cell lymphoid neoplasms. Leuk Lymphoma 1997; 27: 53–63.
Ye BH, Chaganti S, Chang CC, Niu H, Corradini P, Chaganti RS et al. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J 1995; 14: 6209–6217.
Chen W, Iida S, Louie DC, Dalla-Favera R, Chaganti RS . Heterologous promoters fused to BCL6 by chromosomal translocations affecting band 3q27 cause its deregulated expression during B-cell differentiation. Blood 1998; 91: 603–607.
Niu H, Ye BH, Dalla-Favera R . Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev 1998; 12: 1953–1961.
Lossos IS, Jones KD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL et al. The expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood 2001; 98: 945–951.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 1937–1947.
Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C et al. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma [see comments]. N Engl J Med 1994; 331: 74–80.
Kramer MH, Hermans J, Wijburg E, Philippo K, Geelen E, van Krieken JH et al. Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood 1998; 92: 3152–3162.
Ueda C, Uchiyama T, Ohno H . Immunoglobulin (Ig)/BCL6 versus non-Ig/BCL6 gene fusion in diffuse large B-cell lymphoma corresponds to a high- versus low-level expression of BCL6 mRNA. Blood 2002; 99: 2624–2625.
Dallery E, Galiegue-Zouitina S, Collyn-d'Hooghe M, Quief S, Denis C, Hildebrand MP et al. TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3; 4) chromosomal translocation. Oncogene 1995; 10: 2171–2178.
Sideras P, Mizuta TR, Kanamori H, Suzuki N, Okamoto M, Kuze K et al. Production of sterile transcripts of C gamma genes in an IgM-producing human neoplastic B cell line that switches to IgG-producing cells. Int Immunol 1989; 1: 631–642.
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–1392.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.
Schlegelberger B, Metzke S, Harder S, Zühlke-Jenisch R, Zhang Y, Siebert R . Classical and molecular cytogenetics of tumor cells. In: Wegner RD (ed). Diagnostic Cytogenetics. Berlin: Heidelberg: Springer-Verlag, 1999, pp 151–185.
Kikuchi M, Miki T, Kumagai T, Fukuda T, Kamiyama R, Miyasaka N et al. Identification of negative regulatory regions within the first exon and intron of the BCL6 gene. Oncogene 2000; 19: 4941–4945.
Wang X, Li Z, Naganuma A, Ye BH . Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci USA 2002; 99: 15018–15023.
Sanchez-Izquierdo D, Siebert R, Harder L, Marugan I, Gozzetti A, Price HP et al. Detection of translocations affecting the BCL6 locus in B cell non-Hodgkin's lymphoma by interphase fluorescence in situ hybridization. Leukemia 2001; 15: 1475–1484.
Savelyeva L, Mamaeva S . Population analysis of karyotypic heterogeneity of the Raji Burkitt lymphoma cell line. Analysis of 100 karyotypes. Cancer Genet Cytogenet 1988; 34: 63–75.
Knuutila S, Klefstrom J, Szymanska J, Lakkala T, Peltomaki P, Eray M et al. Two novel human B-cell lymphoma lines of lymphatic follicle origin: cytogenetic, molecular genetic and histopathological characterisation. Eur J Haematol 1994; 52: 65–72.
Kubonishi I, Niiya K, Yamashita M, Yano S, Abe T, Ohtsuki Y et al. Characterization of a new human lymphoma cell line (RC-K8) with t(11; 14) chromosome abnormality. Cancer 1986; 58: 1453–1460.
Ueda C, Akasaka T, Kurata M, Maesako Y, Nishikori M, Ichinohasama R et al. The gene for interleukin-21 receptor is the partner of BCL6 in t(3; 16)(q27; p11), which is recurrently observed in diffuse large B-cell lymphoma. Oncogene 2002; 21: 368–376.
Nakamura Y, Miki T, Miura I, Hashimoto K, Miura A, Akimoto K et al. Internal DNA deletion within the BCL-6 gene on untranslocated chromosome in non-Hodgkin's lymphoma with 3q27 abnormality. Leukemia 1996; 10: 658–661.
Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM . BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 2000; 13: 199–212.
Baron BW, Anastasi J, Thirman MJ, Furukawa Y, Fears S, Kim DC et al. The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression: implications for a role of BCL6 in the down-regulation of apoptosis. Proc Natl Acad Sci USA 2002; 99: 2860–2865.
Shvarts A, Brummelkamp TR, Scheeren F, Koh E, Daley GQ, Spits H et al. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. Genes Dev 2002; 16: 681–686.
Lossos IS, Warnke R, Levy R . BCL-6 mRNA expression in higher-grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5′ regulatory region of the BCL6 gene. Leukemia 2002; 16: 1857–1862.
Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti R, Dalla-Favera R . Mutations of the BCL-6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 2003; prepublished online December 19, 2002; DOI 10.1182/blood-2002-11-3387.
Skinnider BF, Horsman DE, Dupuis B, Gascoyne RD . Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities. Hum Pathol 1999; 30: 803–808.
Pittaluga S, Ayoubi TA, Wlodarska I, Stul M, Cassiman JJ, Mecucci C et al. BCL-6 expression in reactive lymphoid tissue and in B-cell non-Hodgkin's lymphomas. J Pathol 1996; 179: 145–150.
Allman D, Jain A, Dent A, Maile RR, Selvaggi T, Kehry MR et al. BCL-6 expression during B-cell activation. Blood 1996; 87: 5257–5268.
Acknowledgements
We thank Dr Stephan Gesk for assistance with FISH analysis. This work was supported by grants CA33399 and CA34233 from the USPHS-NIH and grant FIS 01/0015 from Spanish Ministry of Health. RL is an American Cancer Society Clinical Research Professor.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lossos, I., Akasaka, T., Martinez-Climent, J. et al. The BCL6 gene in B-cell lymphomas with 3q27 translocations is expressed mainly from the rearranged allele irrespective of the partner gene. Leukemia 17, 1390–1397 (2003). https://doi.org/10.1038/sj.leu.2402997
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402997
Keywords
This article is cited by
-
Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma
Cell Death & Disease (2021)
-
Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma
Nature Communications (2014)
-
Ringversuch zum Nachweis genomischer Veränderungen bei Non-Hodgkin-Lymphomen mittels In-situ-Hybridisierung
Der Pathologe (2013)
-
STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas
Oncogene (2007)
-
Two patterns of chromosomal breakpoint locations on the immunoglobulin heavy-chain locus in B-cell lymphomas with t(3;14)(q27;q32): relevance to histology
Oncogene (2006)