61 results on '"Proto-Oncogene Proteins c-bcl-6"'
Search Results
2. U-2932: two clones in one cell line, a tool for the study of clonal evolution
- Author
-
R. A. F. MacLeod, Hans G. Drexler, Robert Geffers, Julia Romani, Margarete Zaborski, Rose-Marie Amini, Stefan Ehrentraut, Stefan Nagel, Hilmar Quentmeier, Michaela Scherr, Mattias Berglund, and Wilhelm G. Dirks
- Subjects
Receptors, CXCR4 ,Cancer Research ,Molecular Sequence Data ,Clone (cell biology) ,Somatic hypermutation ,Biology ,Epigenesis, Genetic ,Immunophenotyping ,Clonal Evolution ,Cell Line, Tumor ,hemic and lymphatic diseases ,Humans ,Epigenetics ,Gene ,Chromosome Aberrations ,Genetics ,Base Sequence ,Genetic heterogeneity ,Oncogenes ,Hematology ,Antigens, CD20 ,BCL6 ,ADP-ribosyl Cyclase 1 ,Molecular biology ,Genes, bcl-2 ,DNA-Binding Proteins ,Oncology ,DNA methylation ,Proto-Oncogene Proteins c-bcl-6 ,Ectopic expression ,Lymphoma, Large B-Cell, Diffuse ,Somatic Hypermutation, Immunoglobulin ,Transcriptome - Abstract
Genetic heterogeneity is common in tumors, explicable by the development of subclones with distinct genetic and epigenetic alterations. We describe an in vitro model for cancer heterogeneity, comprising the diffuse large B-cell lymphoma cell line U-2932 which expresses two sets of cell surface markers representing twin populations flow-sorted by CD20 vs CD38 expression. U-2932 populations were traced to subclones of the original tumor with clone-specific immunoglobulin IgVH4-39 hypermutation patterns. BCL6 was overexpressed in one subpopulation (R1), MYC in the other (R2), both clones overexpressed BCL2. According to the combined results of immunoglobulin hypermutation and cytogenetic analysis, R1 and R2 derive from a mother clone with genomic BCL2 amplification, which acquired secondary rearrangements leading to the overexpression of BCL6 (R1) or MYC (R2). Some 200 genes were differentially expressed in R1/R2 microarrays including transcriptional targets of the aberrantly expressed oncogenes. Other genes were regulated by epigenetic means as shown by DNA methylation analysis. Ectopic expression of BCL6 in R2 variously modulated new candidate target genes, confirming dual silencing and activating functions. In summary, stable retention of genetically distinct subclones in U-2932 models tumor heterogeneity in vitro permitting functional analysis of oncogenes against a syngenic background.
- Published
- 2012
3. Epstein-Barr virus microRNAs repress BCL6 expression in diffuse large B-cell lymphoma
- Author
-
David G. Pisano, R Rodríguez, Santiago Montes-Moreno, Margarita Sánchez-Beato, Pierfrancesco Vargiu, Manuela Mollejo, M A Piris, Lorena Di Lisio, Daniel Martín-Pérez, Josep Castellví, Nerea Martinez, Eduardo Andres Leon, and S M Rodríguez-Pinilla
- Subjects
Herpesvirus 4, Human ,Cancer Research ,Hematology ,Biology ,medicine.disease ,BCL6 ,medicine.disease_cause ,Epstein–Barr virus ,Virus ,BCL10 ,Lymphoma ,DNA-Binding Proteins ,MicroRNAs ,Oncology ,Downregulation and upregulation ,immune system diseases ,hemic and lymphatic diseases ,microRNA ,Immunology ,Proto-Oncogene Proteins c-bcl-6 ,medicine ,Humans ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma - Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30–40% of all newly diagnosed lymphomas. DLBCL is considered a heterogeneous disease, with some specific clinicopathological variants of DLBCLs being associated with the presence of the EBV.1 EBV is a lymphotropic virus that has been implicated in the development of several lymphoid malignancies, mainly Burkitt lymphoma (BL) and Hodgkin's lymphoma and with low prevalence in DLBCL.1 BCL6 is a key transcriptional repressor during normal B-cell differentiation that has been shown to repress NF-kB in some DLBCLs.2 In some B-cell lymphomas, BCL6 expression was inversely correlated with LMP1 expression, and some evidences suggest that LMP1 can cause downregulation of BCL6(ref. 3), but other possible mechanisms have not been studied. We have found a strong inverse correlation between BCL6 protein expression and EBV infection (P
- Published
- 2011
4. Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas
- Author
-
Lynn C. Moscinski, Jianhong Lin, Eduardo M. Sotomayor, Tint Lwin, Kenneth L. Wright, J Tao, Choi Ys, William S. Dalton, Wayne Tam, and Jian Jun Zhao
- Subjects
Cancer Research ,Lymphoma, B-Cell ,Cell Survival ,Down-Regulation ,Cell Communication ,Biology ,Article ,Downregulation and upregulation ,Cell Line, Tumor ,hemic and lymphatic diseases ,PRDM1 ,medicine ,Humans ,Gene silencing ,Antigen-presenting cell ,3' Untranslated Regions ,B cell ,Follicular dendritic cells ,Germinal center ,Hematology ,BCL6 ,Up-Regulation ,DNA-Binding Proteins ,Repressor Proteins ,MicroRNAs ,medicine.anatomical_structure ,Oncology ,Immunology ,Proto-Oncogene Proteins c-bcl-6 ,Cancer research ,Positive Regulatory Domain I-Binding Factor 1 ,Dendritic Cells, Follicular - Abstract
B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell–cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3′UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.
- Published
- 2010
5. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma
- Author
-
George E. Wright, Javeed Iqbal, Lisa M. Rimsza, Lynette M. Smith, Diane L. Pickering, Smrati Jain, Julie M. Vose, Jan Delabie, Timothy C. Greiner, Douglas E. Horsman, Dennis D. Weisenburger, C. P. Hans, Elias Campo, Hans Konrad Müller-Hermelink, Bhavana J. Dave, Yulei Shen, Elaine S. Jaffe, Andreas Rosenwald, Timothy W. McKeithan, Kai Fu, German Ott, Joseph M. Connors, Warren G. Sanger, Louis M. Staudt, K. Patel, J. Ji, Randy D. Gascoyne, and W. C. Chan
- Subjects
Cancer Research ,medicine.medical_specialty ,Time Factors ,DNA Mutational Analysis ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Article ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,RNA, Messenger ,In Situ Hybridization, Fluorescence ,Regulation of gene expression ,Models, Genetic ,Gene Expression Profiling ,Breakpoint ,Cytogenetics ,Germinal center ,Exons ,Hematology ,Prognosis ,medicine.disease ,BCL6 ,Introns ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Treatment Outcome ,Oncology ,Mutation ,Proto-Oncogene Proteins c-bcl-6 ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma - Abstract
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (> 70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
- Published
- 2007
6. Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin
- Author
-
Martine Ffrench, Catherine Thieblemont, Pascale Felman, Gilles Salles, Evelyne Callet-Bauchu, Bertrand Coiffier, Aurélie Verney, Alexandra Traverse-Glehen, Françoise Berger, Jean-Pierre Magaud, and Lucile Baseggio
- Subjects
rho GTP-Binding Proteins ,Cancer Research ,Pathology ,medicine.medical_specialty ,Lymphoma, B-Cell ,PIM1 ,Biology ,B-cell origin ,Proto-Oncogene Proteins c-pim-1 ,immune system diseases ,hemic and lymphatic diseases ,Marginal zone B-cell ,medicine ,Humans ,fas Receptor ,Lymphoma, Follicular ,Splenic Neoplasms ,PAX5 Transcription Factor ,Hematology ,Fas receptor ,medicine.disease ,Marginal zone ,Lymphoma ,DNA-Binding Proteins ,Oncology ,Mutation ,Proto-Oncogene Proteins c-bcl-6 ,PAX5 ,NODAL ,Transcription Factors - Abstract
Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin
- Published
- 2007
7. Clinical and biological relevance of single-nucleotide polymorphisms and acquired somatic mutations of the BCL6 first intron in follicular lymphoma
- Author
-
Jean-Michel Picquenot, Hervé Tilly, Philippe Ruminy, Fabrice Jardin, Françoise Parmentier, Philippe Bertrand, Christian Bastard, G Buchonnet, and Marie-Noëlle Courel
- Subjects
Adult ,Male ,Cancer Research ,DNA Mutational Analysis ,Follicular lymphoma ,Electrophoretic Mobility Shift Assay ,Single-nucleotide polymorphism ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Genotype ,medicine ,Humans ,Lymphoma, Follicular ,Allele frequency ,Gene ,Aged ,Aged, 80 and over ,Chromosomes, Human, Pair 14 ,Gene Rearrangement ,Genetics ,Mutation ,Intron ,DNA ,Hematology ,Middle Aged ,BCL6 ,medicine.disease ,Introns ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Oncology ,Case-Control Studies ,Proto-Oncogene Proteins c-bcl-6 ,Female ,Chromosomes, Human, Pair 3 ,Lymphoma, Large B-Cell, Diffuse ,Chromosomes, Human, Pair 18 ,Transcription Factors - Abstract
Genetic modifications of the BCL6 gene in lymphoma include translocations, deletions, and somatic mutations (SM) of the 5' noncoding region. Three single-nucleotide polymorphisms (SNPs) of the major mutation cluster region (MMC) have been reported, including two substitutions (397G/C, 502G/A) and one deletion (520DeltaT). Clinical and biological relevance of these SNPs are unknown. Based on a case-control study, BCL6 SNPs frequencies were assessed in 97 t(14;18) follicular lymphomas (FL) and in 54 lymphomas with 3q27 rearrangement. Allele frequencies were similar in the FL and controls groups. The 397 G/C genotype was correlated to a higher-grade transformation risk (P=0.02). SM were observed in 39.1% of FL and were characterized by a clustering distribution (hot spots spanning position 420-435, 106-127, and 590-600). No correlation between genotypes or acquired mutational status and BCL6 expression was demonstrated. However, gel mobility-shift assays, using SNPs containing probes show results representative for protein/DNA complexes. This study demonstrates that the first BCL6 intron is a highly variable region as a consequence of both SNP and SM, which may contribute to biology and outcome of FL.
- Published
- 2005
8. Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR
- Author
-
David Oscier, Takashi Sonoki, Tony G. Willis, E L Karran, Martin J. S. Dyer, and Reiner Siebert
- Subjects
Cancer Research ,Lymphoma ,Derivative chromosome ,Molecular Sequence Data ,chemical and pharmacologic phenomena ,Chromosomal translocation ,Molecular cloning ,Biology ,Polymerase Chain Reaction ,Translocation, Genetic ,Proto-Oncogene Proteins c-myc ,immune system diseases ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Cloning, Molecular ,Southern blot ,Chromosomes, Human, Pair 14 ,Gene Rearrangement ,Genetics ,Base Sequence ,Immunoglobulin mu-Chains ,Inverse polymerase chain reaction ,Breakpoint ,PAX5 Transcription Factor ,Nuclear Proteins ,Chromosome Breakage ,Hematology ,Protein-Tyrosine Kinases ,Receptors, Fibroblast Growth Factor ,Molecular biology ,Immunoglobulin Switch Region ,DNA-Binding Proteins ,Repressor Proteins ,Blotting, Southern ,Oncology ,Proto-Oncogene Proteins c-bcl-6 ,Immunoglobulin heavy chain ,PAX5 ,Carrier Proteins ,Immunoglobulin Heavy Chains ,Genes, Switch ,Transcription Factors - Abstract
Molecular cloning of immunoglobulin heavy chain (IGH) translocation breakpoints identifies genes of biological importance in the development of normal and malignant B cells. Long-distance inverse PCR (LDI-PCR) was first applied to amplification of IGH gene translocations targeted to the joining (IGHJ) regions. We report here successful amplification of the breakpoint of IGH translocations targeted to switch (IGHS) regions by LDI-PCR. To detect IGHS translocations, Southern blot assays using 5' and 3' switch probes were performed. Illegitimate Smu rearrangements were amplified from the 5' end (5'Smu LDI-PCR) from the alternative derivative chromosome, and those of Sgamma or Salpha were amplified from the 3' end (3'Sgamma or 3'alpha LDI-PCR) from the derivative chromosome 14. Using a combination of these methods, we have succeeded in amplifying IGHS translocation breakpoints involving FGFR3/MMSET on 4p16, BCL6 on 3q27, MYC on 8q24, IRTA1 on 1q21 and PAX5 on 9p13 as well as BCL11A on 2p13 and CCND3 on 6p21. The combination of LDI-PCR for IGHJ and IGHS allows rapid molecular cloning of almost all IGH gene translocation breakpoints.
- Published
- 2004
9. Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia
- Author
-
Jose A. Martinez-Climent, M. J. Terol, Javier García-Conde, Dolors Sanchez-Izquierdo, Fanny Rubio-Moscardo, Isabel Marugán, Elena Sarsotti, Mar Tormo, and I Benet
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Immunoglobulin Variable Region ,Locus (genetics) ,Biology ,Gene mutation ,Disease-Free Survival ,Germline mutation ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Humans ,B-cell chronic lymphocytic leukemia ,Clinical significance ,Prospective Studies ,Gene ,Aged ,Aged, 80 and over ,Hematology ,Chromosomes, Human, Pair 11 ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,DNA-Binding Proteins ,Mutation ,Immunology ,Proto-Oncogene Proteins c-bcl-6 ,Female ,Chromosome Deletion ,Chromosomes, Human, Pair 17 ,Follow-Up Studies ,Transcription Factors - Abstract
In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was correlated with shorter treatment-free interval (TFI) compared to cases harboring only IgVH mutation (median, 55 months vs not reached; P=0.01), resembling the clinical course of unmutated IgVH cases (median TFI, 44 months). As expected, deletions of 17p13 (P53 locus) and 11q22 (ATM locus) were observed in cases with unmutated IgVH, except one patient who showed mutations of both IgVH and BCL-6. No other statistically significant differences were observed among the genetic subgroups. Our data indicate that BCL-6 mutations identify a subgroup of Binet stage A B-CLL patients with a high risk of progression despite the presence of mutated IgVH gene.
- Published
- 2004
10. The BCL6 gene in B-cell lymphomas with 3q27 translocations is expressed mainly from the rearranged allele irrespective of the partner gene
- Author
-
Jose A. Martinez-Climent, Ronald Levy, Izidore S. Lossos, Takashi Akasaka, and Reiner Siebert
- Subjects
Cancer Research ,Lymphoma, B-Cell ,Biology ,Translocation, Genetic ,immune system diseases ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Gene expression ,Tumor Cells, Cultured ,Humans ,RNA, Messenger ,Allele ,Promoter Regions, Genetic ,Gene ,Alleles ,Gene Rearrangement ,Genetics ,Regulation of gene expression ,Promoter ,Hematology ,Gene rearrangement ,BCL6 ,Neoplasm Proteins ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Oncology ,Regulatory sequence ,Mutation ,Proto-Oncogene Proteins c-bcl-6 ,Cancer research ,Chromosomes, Human, Pair 3 ,Transcription Factors - 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.
- Published
- 2003
11. Follicular lymphoma without t(14;18) and with BCL-6 rearrangement: a lymphoma subtype with distinct pathological, molecular and clinical characteristics
- Author
-
P. Gaulard, Pascal Lenain, G Buchonnet, H. Tilly, Christian Bastard, Françoise Parmentier, C Duval, Nathalie Contentin, Aspasia Stamatoullas, Stéphane Leprêtre, Fabrice Jardin, and Jean-Michel Picquenot
- Subjects
Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,DNA Mutational Analysis ,Follicular lymphoma ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Immunophenotyping ,Cohort Studies ,Immunoenzyme Techniques ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Lymphoma, Follicular ,Aged ,Chromosomes, Human, Pair 14 ,Gene Rearrangement ,Germinal center ,Hematology ,Gene rearrangement ,Middle Aged ,medicine.disease ,Molecular biology ,Lymphoma ,DNA-Binding Proteins ,Survival Rate ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Karyotyping ,Mutation ,Proto-Oncogene Proteins c-bcl-6 ,Female ,Chromosomes, Human, Pair 3 ,CD5 ,Chromosomes, Human, Pair 18 ,Diffuse large B-cell lymphoma ,Transcription Factors - Abstract
Translocations involving the BCL-6 gene are frequently observed in diffuse large B cell lymphoma, but have rarely been reported in follicular lymphoma (FL). We studied a distinct cohort of FLs with a 3q27/BCL-6 gene rearrangement, but lacking the t(14;18) translocation. In 13/15 cases, translocations involved the 3q27 and the 14q32 regions. All cases displayed a marked follicular growth pattern and, in some instances, a monocytoid component. Tumor cells were CD5(-) CD20(+) CD23(-) CD43(-) BCL-6(+), and in the main CD10 negative (n = 10, 71%) and BCL-2 negative (n = 11, 78%). When compared to 20 typical t(14;18)(+) FLs, the presence of large follicles (P = 0.01) and a CD10(-)/BCL-2(-) phenotype were more frequently observed (P = 0.001) in our cohort. Clonal mutations arising in the BCL-6 first intron were observed in 5/7 cases with evidence of intraclonal heterogeneity, consistent with a germinal center origin. No significant difference was found in comparison to t(14;18)(+) FL regarding age, sex, performance status, bone marrow involvement or overall survival. However, in the 3q27(+) FL group, a stage III/IV disease and a bulky mass were less frequently observed. This study indicates that 3q27(+) FL without t(14;18) translocation have peculiar clinico-pathologic features and may correspond to a rare and distinct subtype of lymphoma originating from the germinal center.
- Published
- 2002
12. Characterization of three t(3;8)(q27;q24) translocations from diffuse large B-cell lymphomas
- Author
-
Hervé Tilly, Catherine Maingonnat, Loic Ysebaert, Christian Bastard, Dominique Penther, Philippe Bertrand, Nicole Dastugue, C Maisonneuve, and Jean-Michel Picquenot
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.medical_specialty ,Pathology ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Proto-Oncogene Proteins c-myc ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,B cell ,Hematology ,Cancer ,medicine.disease ,B-cell neoplasm ,body regions ,medicine.anatomical_structure ,Oncology ,Cytogenetic Analysis ,Mutation ,Cancer research ,Proto-Oncogene Proteins c-bcl-6 ,Chromosomes, Human, Pair 3 ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma ,Chromosomes, Human, Pair 8 - Abstract
Characterization of three t(3;8)(q27;q24) translocations from diffuse large B-cell lymphomas
- Published
- 2007
13. T(3;7)(q27;q32) fuses BCL6 to a non-coding region at FRA7H near miR-29
- Author
-
S Winkelmann, Stefan Nagel, R A F MacLeod, Hans G. Drexler, J Bode, B Schneider, and Maren Kaufmann
- Subjects
Male ,Cancer Research ,Lymphoma, B-Cell ,Molecular Sequence Data ,Computational biology ,Biology ,Translocation, Genetic ,Open Reading Frames ,Untranslated Regions ,Sequence Homology, Nucleic Acid ,Tumor Cells, Cultured ,Coding region ,Humans ,RNA, Messenger ,In Situ Hybridization, Fluorescence ,Genetics ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Chromosome Fragile Sites ,Hematology ,Middle Aged ,BCL6 ,DNA-Binding Proteins ,MicroRNAs ,Oncology ,Karyotyping ,Proto-Oncogene Proteins c-bcl-6 ,Chromosomes, Human, Pair 3 ,Lymphoma, Large B-Cell, Diffuse ,Chromosomes, Human, Pair 7 - Published
- 2007
14. Low-grade follicular lymphoma with t(14;18) presents a homogeneous disease entity otherwise the rest comprises minor groups of heterogeneous disease entities with Bcl2 amplification, Bcl6 translocation or other gene aberrances
- Author
-
Koichi Ohshima, Ying Guo, Junji Suzumiya, Kennosuke Karube, Huang Gs, Riko Kawano, and Takahiro Yamaguchi
- Subjects
Genetic Markers ,Cancer Research ,Pathology ,medicine.medical_specialty ,Genotype ,Follicular lymphoma ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,neoplasms ,Gene ,Lymphoma, Follicular ,In Situ Hybridization, Fluorescence ,Chromosomes, Human, Pair 14 ,Gene Abnormality ,Hematology ,medicine.disease ,BCL6 ,Phenotype ,DNA-Binding Proteins ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,Proto-Oncogene Proteins c-bcl-6 ,Chromosomes, Human, Pair 18 - Abstract
Follicular lymphomas (FL) are morphologically classified into grades 1, 2, 3a and 3b by the World Health Organization. Bcl2, Bcl6 and CD10 are phenotypic markers of FL while the Bcl2 t(14;18) and Bcl6 t(3q27) gene translocations are common genetic changes. However, to date, there has been no integrated analysis based on phenotype, grade and genotype from large numbers of FL cases. We graded 261 cases of FL and determined their phenotypes and gene alterations. According to the antigen markers and gene alterations of 147 cases, we classified FL into typical and the others types. The typical group, which includes 69% cases of FL, is characterized by low histological grade (grade 1, 2), coexpression of BCL2 and CD10 and Bcl2 gene translocation. The rest comprises a small part of low-grade FL without Bcl2 gene translocation and high-grade (grade 3a, 3b) FL. These FLs include some heterogeneous disease entities. They are characterized by high histological grade (87%), no definite expression of BCL2 or CD10 and several kinds of gene aberrances including Bcl2 translocation, Bcl6 translocation, Bcl2 amplification or other unknown gene abnormality. Our findings indicate that typical FL presents a homogeneous disease entity whereas the rest comprises heterogeneous diseases entities.
- Published
- 2005
15. AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity
- Author
-
Ash A. Alizadeh, I. S. Lossos, and Ronald Levy
- Subjects
Cancer Research ,medicine.medical_specialty ,Pathology ,Lymphoma, B-Cell ,Immunoglobulin Variable Region ,Cytosine Deaminase ,Germline mutation ,Internal medicine ,Cytidine Deaminase ,medicine ,Activation-induced (cytidine) deaminase ,Tumor Cells, Cultured ,Humans ,Lymphoma, Follicular ,B cell ,Hematology ,biology ,Large cell ,Large-cell lymphoma ,Germinal cell ,Germinal center ,medicine.disease ,Germinal Center ,Molecular biology ,Leukemia, Lymphocytic, Chronic, B-Cell ,DNA-Binding Proteins ,medicine.anatomical_structure ,Oncology ,biology.protein ,Proto-Oncogene Proteins c-bcl-6 ,Lymphoma, Large B-Cell, Diffuse ,Somatic Hypermutation, Immunoglobulin ,Immunoglobulin Heavy Chains - Abstract
Activation-induced cytidine deaminase (AID), highly expressed in germinal center (GC)-lymphocytes, is involved in somatic hypermutation (SHM). We examined AID expression in diffuse large B-cell lymphomas (DLBCL) of germinal center B-cell (GCB)-like and activated B-cell (ABC)-like subtypes. These two types of DLBCL are characterized by high and low expression of GC-specific genes, respectively. AID expression was detected in both GCB- and ABC-like DLBCL, thus demonstrating a dissociation between AID expression and that of other GC genes. We also tested for the presence of intraclonal heterogeneity in immunoglobulin and BCL6 genes in those same tumors and in follicle center lymphomas (FCL) that transformed to DLBCL. The level of AID expression did not correlate with the presence of intraclonal sequence heterogeneity in either IgV(H) or BCL6. Our findings suggest that lymphomas maintain some but not all of the gene expression signatures of their normal B-cell counterparts. The fact that AID expression can be elevated without intraclonal sequence heterogeneity raises the possibility that other factors are required for SHM in these tumors. We found decreased levels of AID expression in DLBCL that evolved from FCL and which had acquired new mutations in their BCL6 genes. This dissociation suggests that AID expression and SHM may occur at the time prior to the clinical detection of transformed lymphoma.
- Published
- 2004
16. Diagnostic role and prognostic significance of a simplified immunophenotypic classification of mature B cell chronic lymphoid leukemias
- Author
-
Agostino Cortelezzi, Maria Goldaniga, Daniela Intini, A. Guffanti, M.G. Grimoldi, C Patriarca, Mariangela Colombi, L. Cro, Luca Baldini, Antonino Neri, Anna Teresa Maiolo, and Bruno Mario Cesana
- Subjects
Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Mature B-Cell ,Blotting, Western ,Immunoglobulins ,CD5 Antigens ,Sensitivity and Specificity ,Prognostic stratification ,Immunophenotyping ,Antigens, CD ,Lectins ,Proto-Oncogene Proteins ,Medicine ,Humans ,Lymphocytes ,Aged ,Aged, 80 and over ,Chromosome Aberrations ,business.industry ,Receptors, IgE ,Membrane Proteins ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Genes, bcl-1 ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Oncology ,Karyotyping ,Proto-Oncogene Proteins c-bcl-6 ,Female ,business ,Follow-Up Studies ,Transcription Factors - Abstract
We verified the diagnostic and prognostic role of a simplified immunophenotypic classification (IC) in a series of 258 patients (M/F: 1.4; median age: 64 years; median follow-up: 64 months; 75 deaths) with mature B cell lymphoid leukemias (MBC-LL) for whom no histopathological diagnosis was available because of minimal or no lymph node involvement. The IC was based on the reactivity of three pivotal immunophenotypic markers: CD5, CD23 and SIg intensity. On the basis of different expression patterns, we identified four diagnostic clusters (C) characterized by distinct clinico-biological features and different prognoses: C1 (149 patients) identified most classical B cell chronic lymphocytic leukemias (CLL-type cluster; SIg(dim)/CD5+/CD23+); C2, 38 patients whose clinico-hematological characteristics were intermediate between C1 and C3 (CLL-variant cluster; SIg(bright)/CD5+/CD23+/-or SIg(dim)/CD5-/-/CD23 indifferent); C3 (16 patients) most situations consistent with mantle cell lymphoma in leukemic phase (MCL-type cluster; SIg(bright)/CD5+/CD23-); and C4, 55 cases, most of whom were consistent with leukemic phase lymphoplasmacytic/splenic marginal zone lymphomas (LP/S-type cluster; SIg(bright)/CD5-/+/CD23 indifferent). At univariate survival analysis, prognosis worsened from C1 to C4, C2 and C3 (P = 0.0001), and this was maintained at multivariate analysis (P = 0.006), together with CD11c expression (P = 0.0043), age at diagnosis (cut-off 70 years; P = 0.0008) and platelet count (cut-off 140 x 10(9)/l; P = 0.0034). Besides recognising the two well-known situations of classic B-CLL and MCL, our IC identified situations with distinct prognostic and/or clinical behaviors.
- Published
- 2002
17. Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements
- Author
-
Nathalie Contentin, Jean-Michel Picquenot, Philippe Bertrand, Françoise Parmentier, Pascal Lenain, Aspasia Stamatoullas, G Buchonnet, H. Tilly, Christian Bastard, Fabrice Jardin, Stéphane Leprêtre, J. D’Anjou, and S. Laberge
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Biopsy ,Follicular lymphoma ,Chromosomal translocation ,Lymphoma, Mantle-Cell ,Biology ,Translocation, Genetic ,immune system diseases ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,medicine ,Tumor Cells, Cultured ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Lymphoma, Follicular ,B cell ,DNA Primers ,Chromosome Aberrations ,Gene Rearrangement ,Gene Expression Regulation, Leukemic ,Reverse Transcriptase Polymerase Chain Reaction ,Large-cell lymphoma ,Germinal center ,Hematology ,Gene rearrangement ,medicine.disease ,Molecular biology ,Hodgkin Disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Lymphoma ,Up-Regulation ,DNA-Binding Proteins ,Blotting, Southern ,medicine.anatomical_structure ,Oncology ,Proto-Oncogene Proteins c-bcl-6 ,Chromosomes, Human, Pair 3 ,Lymph Nodes ,Transcription Factors - Abstract
The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27(+) DLBCL (n = 20) cases and 67% of 3q27(+) cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 +/- 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 +/- 1.82; P0.001), MCL (1.23 +/- 0.73), MZL (1.49 +/- 1.3), HD (1.60 +/- 1.00), TCL (1.75 +/- 1.64), but also RH (3.91 +/- 3.12) or NM (1.95 +/- 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P0.001). Conversely, we failed to show any difference between 3q27(+) DLBCL and 3q27(-)DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27(+) FCL (n = 10) was significantly lower than in 3q27(-) FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.
- Published
- 2002
18. BCL-6 mRNA expression in higher grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5' regulatory region of the BCL-6 gene
- Author
-
Ronald Levy, Izidore S. Lossos, and Roger A. Warnke
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Lymphoma, B-Cell ,Follicular lymphoma ,Biology ,Gene mutation ,Polymerase Chain Reaction ,Immunoenzyme Techniques ,Germline mutation ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Gene expression ,medicine ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Lymphoma, Follicular ,B cell ,DNA Primers ,Point mutation ,Hematology ,medicine.disease ,Molecular biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,Regulatory sequence ,Mutation ,Proto-Oncogene Proteins c-bcl-6 ,Lymphoma, Large B-Cell, Diffuse ,5' Untranslated Regions ,Diffuse large B-cell lymphoma ,Transcription Factors - Abstract
Follicle center lymphoma (FCL) is an indolent low-grade B cell non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive diffuse large B cell lymphoma (DLBCL). Histological transformation of FCL is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is commonly implicated in the pathogenesis of DLBCL and its expression may be altered by clonal rearrangements and somatic point mutations in its 5' non-translated regulatory region. Recently, somatic mutations of the BCL-6 gene were associated with the transformation process. Here, we examined BCL-6 mRNA expression and BCL-6 mutations in paired biopsies from the same patients obtained at the time of FCL diagnosis and after transformation. BCL-6 mRNA expression markedly increased upon transformation (1.9- to 4.8-fold) in three cases, remained unchanged in one case and decreased compared to the diagnosis FCL specimens in four cases. The three specimens that demonstrated an increase in the BCL-6 mRNA expression upon transformation harbored BCL-6 gene mutations in the 5' region of the first intron that overlapped with the previously reported negative regulatory region of the gene. Accumulation of new mutations in this region was not observed in DLBCL biopsies in which the BCL-6 mRNA expression did not increase. The present study demonstrates that although BCL-6 gene mutations do accumulate during the transformation process and, depending on their location within the first intron, may deregulate BCL-6 mRNA expression, increase in BCL-6 mRNA expression is not uniformly required for transformation from FCL to DLBCL.
- Published
- 2001
19. Molecular heterogeneity of splenic marginal zone lymphomas: analysis of mutations in the 5' non-coding region of the bcl-6 gene
- Author
-
Villuendas R, Marisol Mateo, Margarita Sánchez-Beato, M A Piris, Pedro Javier Gómez Martínez, Manuela Mollejo, and Patrocinio Algara
- Subjects
Cancer Research ,Lymphoma, B-Cell ,Marginal zone lymphoma ,Spleen ,Biology ,Molecular heterogeneity ,Germline mutation ,NAD+ Nucleosidase ,Antigens, CD ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,medicine ,Coding region ,Humans ,ADP-ribosyl Cyclase ,Gene ,Genetics ,Membrane Glycoproteins ,Splenic Neoplasms ,Hematology ,Molecular biology ,ADP-ribosyl Cyclase 1 ,Antigens, Differentiation ,Leukemia, Lymphocytic, Chronic, B-Cell ,DNA-Binding Proteins ,medicine.anatomical_structure ,Oncology ,Mutation ,Splenic Marginal Zone ,Proto-Oncogene Proteins c-bcl-6 ,5' Untranslated Regions ,Transcription Factors - Abstract
Splenic marginal zone lymphoma (SMZL) has been recognized as a distinctive type of small B cell lymphoma, and defined on the basis of its morphological, phenotypic, clinical and molecular characteristics. In spite of this, the borders of the entity, the homogeneity of the cases and the presumably cell origin of SMZL remain controversial issues. The frequency of mutation in the 5' non-coding region of the bcl-6 gene has been used as a marker of germinal center derivation, which may be used to establish the molecular heterogeneity of different non-Hodgkin lymphoma (NHL) types. This roughly parallels the characteristics and frequency of the somatic hypermutations found in the immunoglobulin heavy chain variable region (IgVH) genes. This study analyzed mutations of bcl-6 in the 5' non-coding region in 22 SMZL cases and, for the purpose of comparison with different B cell subsets, in microdissected germinal centers, mantle zones and marginal zone subpopulations from reactive splenic lymphoid follicles. A majority of the SMZL cases studied, 19/22 (87%), bear unmutated bcl-6 gene, while mutation was only observed in 3/22 (13%) cases. Analysis of normal B cell subpopulations showed bcl-6 hypermutation in 3/10 (30%) germinal center clones, 5/14 (35%) marginal zone clones; and unmutated sequences in all clones derived from mantle cells. The frequency of these mutations in normal spleen confirms previous findings on the hypermutation IgVH process in normal B cell populations. The data presented here support the existence of molecular heterogeneity in this entity, and give additional results in favor of the hypothesis that, in spite of initial morphological observations, a significant proportion of SMZL cases could derive from an unmutated naive precursor, different from the marginal zone, and possibly located in the mantle zone of splenic lymphoid follicles. Thus the marginal zone differentiation of these tumors could be related more with the splenic microenvironment than it is to the histogenetic characteristics of the tumor.
- Published
- 2001
20. De novo acute B cell leukemia/lymphoma with t(14;18)
- Author
-
Pascal Lenain, P. Gaulard, G Buchonnet, Aspasia Stamatoullas, M.P. Callat, Bernard Lenormand, C Duval, Hervé Tilly, Stéphane Leprêtre, and Christian Bastard
- Subjects
Male ,Cancer Research ,Pathology ,Follicular lymphoma ,Genes, myc ,Translocation, Genetic ,Immunophenotyping ,Meninges ,Bone Marrow ,Recurrence ,hemic and lymphatic diseases ,Treatment Failure ,Lymphoma, Follicular ,Bone Marrow Transplantation ,Large-cell lymphoma ,Hematology ,DNA, Neoplasm ,Middle Aged ,Neoplastic Cells, Circulating ,Prognosis ,Burkitt Lymphoma ,DNA-Binding Proteins ,Leukemia ,medicine.anatomical_structure ,Oncology ,Disease Progression ,Proto-Oncogene Proteins c-bcl-6 ,Female ,Adult ,medicine.medical_specialty ,Lymphoma, B-Cell ,Antineoplastic Agents ,Biology ,Leukemic Infiltration ,Acute lymphocytic leukemia ,Proto-Oncogene Proteins ,medicine ,Humans ,B cell ,Chromosomes, Human, Pair 14 ,Salvage Therapy ,medicine.disease ,Genes, p53 ,Lymphoma ,Genes, bcl-2 ,B-cell leukemia ,Blast Crisis ,Chromosomes, Human, Pair 18 ,Transcription Factors - Abstract
The t(14;18)(q32;q21) translocation is the most common translocation in B cell malignancies being found in 80% of follicular lymphomas and about 20% of diffuse large B cell lymphomas. Only rare cases of de novo acute B cell lymphoblastic leukemia with t(14;18) have been described. We describe five cases of this entity which appears to have very homogeneous clinical, phenotypic and genotypic features. None of these patients had prior history of follicular lymphoma. The disease was characterized by acute clinical features with nodal and/or extranodal disease, massive bone marrow infiltration and rapid increase of circulating blast cells of mature B cell phenotype. All patients disclosed complex chromosomal and molecular abnormalities involving at least the BCL-2 and c-MYC genes. Furthermore, three patients had evidence of BCL-6 involvement and one patient had a p53 mutation. Despite intensive chemotherapy, including for two patients allogeneic bone marrow transplantation in first complete remission, all patients died within a few months. Neuro-meningeal relapse occurred in three of the five patients in spite of neuro-meningeal prophylaxis. De novo leukemia/lymphoma with t(14;18) is a rare entity with a very poor prognosis. Whether early bone marrow transplant could modify the natural history of the disease remains to be determined. An intensive neuro-meningeal prophylaxis appears to be mandatory in these patients.
- Published
- 2000
21. Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes
- Author
-
Daniela Capello, Nicholas Chiorazzi, Franco Fais, Manlio Ferrarini, Gianluca Gaidano, G Migliaretti, and Daniela Vivenza
- Subjects
Cancer Research ,BCL-6 ,Chronic lymphocytic leukemia ,Immunoglobulin Variable Region ,Biology ,medicine.disease_cause ,Proto-Oncogene Mas ,Chronic lymphocytyc leukemia ,Germline mutation ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Proto-Oncogenes ,medicine ,Tumor Cells, Cultured ,Humans ,Point Mutation ,Gene Rearrangement, B-Lymphocyte ,B cell ,Genetics ,Mutation ,Base Sequence ,Genes, Immunoglobulin ,Somatic mutation ,Point mutation ,Germinal center ,Zinc Fingers ,Hematology ,Gene rearrangement ,medicine.disease ,Molecular biology ,Leukemia, Lymphocytic, Chronic, B-Cell ,DNA-Binding Proteins ,Leukemia ,medicine.anatomical_structure ,Oncology ,Immunoglobulin variable region ,Proto-Oncogene Proteins c-bcl-6 ,Immunoglobulin Light Chains ,Immunoglobulin Heavy Chains ,Transcription Factors - Abstract
Although B cell chronic lymphocytic leukemia (B-CLL) has been traditionally viewed as a tumor of virgin B cells, this notion has been recently questioned by data suggesting that a fraction of B-CLL derives from antigen experienced B cells. In order to further clarify the histogenetic derivation of this lymphoproliferation, we have analyzed the DNA sequences of the 5' non-coding region of BCL-6 proto-oncogene in 28 cases of B-CLL. Mutations of BCL-6 proto-oncogene, a zinc finger transcription factor implicated in lymphoma development, represent a histogenetic marker of B cell transit through the germinal center (GC) and occur frequently in B cell malignancies derived from GC or post-GC B cells. For comparison, the same tumor panel was analyzed for somatic mutations of the rearranged immunoglobulin variable (IgV) genes, which are known to be acquired at the time of B cell transit through the GC. Sequence analyses of BCL-6 and IgV genes allowed the definition of three groups of B-CLL. Group I B-CLL displayed mutations of both BCL-6 and IgV genes (10/28; 36%). Group II B-CLL displayed mutated IgV genes, but a germline BCL-6 gene (5/28; 18%). Finally, group III B-CLL included the remaining cases (13/28; 46%) that were characterized by the absence of somatic mutations of both BCL-6 and IgV genes. Overall, the distribution of BCL-6 and IgV mutations in B-CLL reinforce the notion that this leukemia is histogenetically heterogeneous and that a substantial subgroup of these lymphoproliferations derives from post-germinal center B cells.
- Published
- 2000
22. MUM1: a step ahead toward the understanding of lymphoma histogenesis
- Author
-
Alessia Carbone and Gianluca Gaidano
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Lymphoma, B-Cell ,Cellular differentiation ,Plasma Cells ,Somatic hypermutation ,Biology ,Histogenesis ,Models, Biological ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,medicine ,Biomarkers, Tumor ,Humans ,Neoplastic transformation ,B-cell lymphoma ,B cell ,Genes, Immunoglobulin ,Germinal center ,Cell Differentiation ,Hematology ,medicine.disease ,Germinal Center ,Lymphoma ,DNA-Binding Proteins ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Phenotype ,Oncology ,Interferon Regulatory Factors ,Mutation ,Cancer research ,Proto-Oncogene Proteins c-bcl-6 ,Transcription Factors - Abstract
In recent times, the field of B cell lymphoma histogenesis has progressed rapidly due to the increasing availability of histogenetic markers. Genotypic markers of B cell histogenesis are represented by mutations of IgV and BCL-6 genes, which are somatically acquired at the time of B cell transit through the germinal center (GC). Phenotypic markers are represented by BCL-6 and CD138/syndecan-1 protein expression and allow the distinction between GC and post-GC B cells. On this basis, lymphomas may be histogenetically distinguished into: (1) lymphomas devoid of somatic IgV and BCL-6 hypermutation, which derive from pre-germinal center B cells; (2) lymphomas associated with somatic IgV and/or BCL-6 hypermutation and BCL-6 expression, which closely reflect germinal center B cells; and (3) lymphomas associated with somatic IgV and/or BCL-6 hypermutation, as well as CD138/syndecan-1 positivity, representing lymphomas of post-germinal center B cells. In the March issue of Leukemia, Tsuboi et al report on the expression pattern of MUM1 in normal lymphoid tissues and in lymphoma. Because expression of MUM1 protein appears to be strictly regulated during lymphoid differentiation, and because expression of the molecule is retained upon neoplastic transformation, MUM1 may be added to the panel of phenotypic markers of B cell lymphoma histogenesis. In particular, MUM1 may provide a marker for the identification of transition from BCL-6 positivity (GC B cells) to CD138 expression (immunoblasts and plasma cells). These studies are of potential clinical value, since in some B cell malignancies, histogenesis may influence prognosis.
- Published
- 2000
23. Regulation of BCL-6 gene expression in human myeloid/monocytoid leukemic cells
- Author
-
Akira B. Miura, Shigeo Mori, Masatsugu Moriyama, Tadanori Yamochi, A Kitabayashi, Toshiko Onizuka, and M Hirokawa
- Subjects
Adult ,Cancer Research ,Myeloid ,Transcription, Genetic ,Cellular differentiation ,HL-60 Cells ,Cycloheximide ,Biology ,Flow cytometry ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,Gene expression ,medicine ,Tumor Cells, Cultured ,Humans ,Regulation of gene expression ,Cell Nucleus ,medicine.diagnostic_test ,Cell Differentiation ,Hematology ,medicine.disease ,Flow Cytometry ,Molecular biology ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Cell nucleus ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,chemistry ,Immunology ,Dactinomycin ,Proto-Oncogene Proteins c-bcl-6 ,Tetradecanoylphorbol Acetate ,Transcription Factors - Abstract
We demonstrated in the present study that the BCL-6 transcripts were detectable not only in B cells, but also in circulating granulocytes and monocytes from normal individuals, and in human acute nonlymphocytic leukemia cells of certain subtypes (M3, M4, M5). Then, with an assumption that the BCL-6 gene expression may be related to the differentiation of myeloid cells, we analyzed the inducibility of BCL-6 gene expression along monocytic lineage differentiation in HL-60 and U-937 cells by treating them with 12-O-tetradecanoylphorbol-13-acetate (TPA). Although the expression of BCL-6 transcripts was very low or undetectable in untreated HL-60 or U-937 cells, treatment of these cells with TPA to induce monocytic differentiation resulted in an apparent increase of BCL-6 mRNA, suggesting that BCL-6 gene expression is not limited to B cells and it is closely associated with monocytic lineage differentiation. The BCL-6 transcripts in TPA-treated U-937 cells were superinduced by the treatment with cycloheximide (CHX) and the half-life of the BCL-6 mRNA was apparently prolonged when TPA-treated U-937 cells were exposed to CHX in the presence of actinomycin D (ACD). Furthermore, the nuclear run-on assay revealed that the BCL-6 transcription signals were enhanced by TPA treatment. These results suggest that the increase of BCL-6 mRNA in U-937 cells stimulated with TPA to induce monocytic lineage differentiation is mediated by both transcriptional and post-transcriptional regulation.
- Published
- 1997
24. Rapid detection of lymphoma-specific translocations in interphase nuclei of non-Hodgkin's lymphoma by fluorescence in situ hybridization
- Author
-
M, Taniwaki, Y, Ueda, K, Nishida, T, Takashima, K, Kashima, F, Matsuda, and G A, Silverman
- Subjects
Cell Nucleus ,Chromosomes, Human, Pair 14 ,Gene Rearrangement ,Lymphoma, B-Cell ,Genes, Immunoglobulin ,Chromosomes, Human, Pair 11 ,Chromosome Mapping ,Translocation, Genetic ,DNA-Binding Proteins ,Proto-Oncogene Proteins ,Proto-Oncogene Proteins c-bcl-6 ,Humans ,Chromosomes, Human, Pair 3 ,Chromosomes, Human, Pair 18 ,DNA Probes ,Interphase ,In Situ Hybridization, Fluorescence ,Transcription Factors - Abstract
We have recently developed a method to detect tumor-specific rearrangement of the IgH gene in interphase nuclei by fluorescence in situ hybridization. Tumor-specific IgH gene rearrangement is equivalent to 14q32.33 translocation. Using this approach, we detected 14q32.33 translocation in 29 of 70 patients with B-cell non-Hodgkin's lymphoma (NHL). Chromosome t(3;14) was found in 10 of these 29 patients, and were demonstrated as a fusion signal of BCL6 and VH gene probes in interphase nuclei. Furthermore, in another series of 11 patients and a NHL cell line, we demonstrated t(14;18) and t(11;14) in interphase and metaphase cells with a combination of BCL2 (or PRAD1) with IgH gene probes. Interphase FISH with lymphoma-associated gene probes is a rapid procedure for cytogenetic diagnosis of B-cell NHL.
- Published
- 1997
25. Rearrangement of the BCL6 gene in B-cell lymphoid neoplasms
- Author
-
M, Muramatsu, T, Akasaka, N, Kadowaki, H, Ohno, S, Fukuhara, and M, Okuma
- Subjects
Gene Rearrangement ,Lymphoma, B-Cell ,Lymphoma, Non-Hodgkin ,Chromosome Mapping ,Zinc Fingers ,Chromosome Banding ,DNA-Binding Proteins ,Bone Marrow ,Proto-Oncogene Proteins ,Proto-Oncogene Proteins c-bcl-6 ,Humans ,Chromosomes, Human, Pair 3 ,Lymphoma, Large B-Cell, Diffuse ,Lymphoma, Follicular ,Transcription Factors - Abstract
We report here a large series of B-cell neoplasms with regard to rearrangement of the BCL6 gene on chromosome band 3q27. Southern blot analysis using probes from the major translocation cluster (MTC) region of the BCL6 revealed rearrangement in 32 of a total of 222 patients with various subtypes of B-cell neoplasm. In non-Hodgkin's lymphoma (NHL), rearrangements of the BCL6 gene were not closely associated with a specific histopathologic subtype but distributed in subcategories in the Working Formulation. A comparative study between NHL associated either with BCL2 or BCL6 rearrangement showed that advanced disease and bone marrow involvement were more frequent in BCL2(+) NHL. In contrast, extranodal involvement was more frequently observed in the BCL6(+) NHL. The survival curve of BCL6(+) NHL was characterized by a rapid decline followed by a plateau. Of the total of 32 BCL6(+) patients, 6 carried both BCL2 and BCL6 rearrangements, and showed clinicopathological properties of follicular lymphoma. This study suggests that BCL6 rearrangement is primarily associated with large cell lymphoma, and that BCL2(-)BCL6(+) NHL could potentially be curable with modern combination chemotherapy.
- Published
- 1997
26. Long distance polymerase chain reaction for detection of chromosome translocations in B-cell lymphoma/leukemia
- Author
-
T, Akasaka, H, Ohno, T, Mori, and M, Okuma
- Subjects
Chromosomes, Human, Pair 14 ,Lymphoma, B-Cell ,Genes, myc ,Chromosome Mapping ,DNA, Neoplasm ,Exons ,Burkitt Lymphoma ,Polymerase Chain Reaction ,Translocation, Genetic ,DNA-Binding Proteins ,B-Cell Lymphoma 3 Protein ,Proto-Oncogene Proteins ,Proto-Oncogenes ,Leukemia, B-Cell ,Proto-Oncogene Proteins c-bcl-6 ,Chromosomes, Human ,Humans ,Chromosomes, Human, Pair 8 ,DNA Primers ,Transcription Factors - Abstract
To establish a rapid and sensitive method to detect neoplastic cells carrying a specific chromosomal translocation in B-cell lymphoma/leukemia, we have developed a novel strategy based on long distance polymerase chain reaction (LD-PCR) amplification. Genomic DNA were extracted from tumor cells carrying a t(14;19)(q32;q13), a t(8;14)(q24;q32), a t(3;22)(q27;q11), a t(2;3)(p12;q27), and a t(3;14)(q27;q32). Oligonucleotide primer pairs were designed to be complementary to exons or flanking sequences of the BCL3, c-MYC and BCL6 oncogenes, and to constant region genes of the IG genes. LD-PCR with a newly available Taq polymerase for longer product synthesis successfully amplified fragments representing BCL3/C alpha junctional sequences for t(14;19); c-MYC/C mu, c-MYC/C gamma and c-MYC/C alpha for t(8;14); BCL6/C lambda for t(3;22); BCL6/C kappa for t(2;3); 5'-BCL6/C mu and 5'-BCL6/C gamma for t(3;14), respectively. The sizes of the amplified fragments were varied from 1.8 kb to 12 kb, which were specific to each material. Present study provides a useful tool for diagnosis and subsequent management of B-cell lymphoma/leukemia characterized with specific chromosomal translocation.
- Published
- 1997
27. The B cell transcriptional coactivator BOB1/OBF1 gene fuses to the LAZ3/BCL6 gene by t(3;11)(q27;q23.1) chromosomal translocation in a B cell leukemia line (Karpas 231)
- Author
-
S, Galiègue Zouitina, S, Quief, M P, Hildebrand, C, Denis, G, Lecocq, M, Collyn-d'Hooghe, C, Bastard, M, Yuille, M J, Dyer, and J P, Kerckaert
- Subjects
DNA, Complementary ,Molecular Sequence Data ,Restriction Mapping ,Gene Expression ,Regulatory Sequences, Nucleic Acid ,Polymerase Chain Reaction ,Translocation, Genetic ,Cell Line ,Proto-Oncogene Proteins ,Leukemia, B-Cell ,Tumor Cells, Cultured ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,DNA Primers ,Base Sequence ,Genes, Immunoglobulin ,Chromosomes, Human, Pair 11 ,Chromosome Mapping ,Zinc Fingers ,Exons ,Introns ,DNA-Binding Proteins ,Proto-Oncogene Proteins c-bcl-6 ,Trans-Activators ,Chromosomes, Human, Pair 3 ,Transcription Factors - Abstract
The LAZ3/BCL6 gene on chromosone 3q27 is recurrently disrupted in B cell non-Hodgkin's lymphomas by translocations involving immunoglobulin genes or other chromosone regions. We have cloned the breakpoint region and chromosone derivatives of the t(3;11)(q27;q23.1) translocation, present in a B cell leukemia cell line (Karpas 231), which define a novel 11q23.1 breakpoint site. As a consequence of the translocation, LAZ3 regulatory regions upstream of non-coding exon 2 are replaced by those of BOB1/OBF1, a recently described B cell-specific coactivator of octamer-binding transcription factors. A detailed structural study of the BOB1/OBF1 genomic DNA and of a nearly full-length cDNA revealed particular features in the 3' untranslated region, such as an Alu motif and a polymorphic tetranucleotide microsatellite. Two mutations leading to two potential amino acid changes in the C-terminal region, were also detected in one allele of a lymphoma B cell line, Raji. Due to its cell-specific expression and role as a coactivating transcription factor, chromosomal translocation and/or point mutation of BOB1/OBF1 may contribute to B cell tumorigenesis.
- Published
- 1996
28. Internal DNA deletion within the BCL-6 gene on untranslocated chromosome in non-Hodgkin's lymphoma with 3q27 abnormality
- Author
-
Y, Nakamura, T, Miki, I, Miura, K, Hashimoto, A, Miura, K, Akimoto, S, Hirosawa, K, Saito, H, Enokihara, S, Furusawa, and H, Shishido
- Subjects
Chromosome Aberrations ,Male ,Base Sequence ,Molecular Sequence Data ,Restriction Mapping ,Chromosome Mapping ,Chromosome Disorders ,Zinc Fingers ,DNA, Neoplasm ,Middle Aged ,Hodgkin Disease ,Polymerase Chain Reaction ,Translocation, Genetic ,DNA-Binding Proteins ,Proto-Oncogene Proteins ,Proto-Oncogenes ,Proto-Oncogene Proteins c-bcl-6 ,Humans ,Chromosomes, Human, Pair 3 ,DNA Primers ,Sequence Deletion ,Transcription Factors - Abstract
Chromosomal translocations involving the band 3q27 are recognized as common specific cytogenetic abnormalities in B cell non-Hodgkin's lymphoma (NHL), and the BCL-6 gene, identified on 3q27 was shown to be disrupted by these translocations. Previously, we have reported biallelic BCL-6 rearrangements occurring in some patients with B cell NHL. In the present study, we describe a NHL patient with t(3;22)(q27;q11) translocation. In this patient, biallelic BCL-6 abnormalities were indicated by Southern blot analysis. Further studies revealed that one of the two independent abnormalities was a juxtaposition to the immunoglobulin (Ig) lambda gene associated with chromosomal translocation, whereas the other was an internal DNA deletion of 1.5 kb area on untranslocated chromosome 3. Deletion junctions were located within the first exon and the 5' region of the first intron. The result provides the evidence that, besides chromosomal translocation, submicroscopic local DNA recombination can cause structural alteration of the BCL-6 gene.
- Published
- 1996
29. U-2932: two clones in one cell line, a tool for the study of clonal evolution.
- Author
-
Quentmeier H, Amini RM, Berglund M, Dirks WG, Ehrentraut S, Geffers R, Macleod RA, Nagel S, Romani J, Scherr M, Zaborski M, and Drexler HG
- Subjects
- ADP-ribosyl Cyclase 1 analysis, Antigens, CD20 analysis, Base Sequence, Cell Line, Tumor, Chromosome Aberrations, DNA-Binding Proteins genetics, Epigenesis, Genetic, Genes, bcl-2, Humans, Immunophenotyping, Lymphoma, Large B-Cell, Diffuse immunology, Molecular Sequence Data, Oncogenes, Proto-Oncogene Proteins c-bcl-6, Receptors, CXCR4 genetics, Somatic Hypermutation, Immunoglobulin, Transcriptome, Clonal Evolution, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Genetic heterogeneity is common in tumors, explicable by the development of subclones with distinct genetic and epigenetic alterations. We describe an in vitro model for cancer heterogeneity, comprising the diffuse large B-cell lymphoma cell line U-2932 which expresses two sets of cell surface markers representing twin populations flow-sorted by CD20 vs CD38 expression. U-2932 populations were traced to subclones of the original tumor with clone-specific immunoglobulin IgVH4-39 hypermutation patterns. BCL6 was overexpressed in one subpopulation (R1), MYC in the other (R2), both clones overexpressed BCL2. According to the combined results of immunoglobulin hypermutation and cytogenetic analysis, R1 and R2 derive from a mother clone with genomic BCL2 amplification, which acquired secondary rearrangements leading to the overexpression of BCL6 (R1) or MYC (R2). Some 200 genes were differentially expressed in R1/R2 microarrays including transcriptional targets of the aberrantly expressed oncogenes. Other genes were regulated by epigenetic means as shown by DNA methylation analysis. Ectopic expression of BCL6 in R2 variously modulated new candidate target genes, confirming dual silencing and activating functions. In summary, stable retention of genetically distinct subclones in U-2932 models tumor heterogeneity in vitro permitting functional analysis of oncogenes against a syngenic background.
- Published
- 2013
- Full Text
- View/download PDF
30. Epstein-Barr virus microRNAs repress BCL6 expression in diffuse large B-cell lymphoma.
- Author
-
Martín-Pérez D, Vargiu P, Montes-Moreno S, León EA, Rodríguez-Pinilla SM, Lisio LD, Martínez N, Rodríguez R, Mollejo M, Castellvi J, Pisano DG, Sánchez-Beato M, and Piris MA
- Subjects
- Humans, Lymphoma, Large B-Cell, Diffuse virology, Proto-Oncogene Proteins c-bcl-6, DNA-Binding Proteins metabolism, Herpesvirus 4, Human genetics, Lymphoma, Large B-Cell, Diffuse metabolism, MicroRNAs genetics
- Published
- 2012
- Full Text
- View/download PDF
31. Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas.
- Author
-
Lin J, Lwin T, Zhao JJ, Tam W, Choi YS, Moscinski LC, Dalton WS, Sotomayor EM, Wright KL, and Tao J
- Subjects
- 3' Untranslated Regions physiology, Cell Communication, Cell Line, Tumor, Cell Survival, Down-Regulation, Humans, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Up-Regulation, DNA-Binding Proteins genetics, Dendritic Cells, Follicular physiology, Lymphoma, B-Cell metabolism, MicroRNAs physiology, Repressor Proteins genetics
- Abstract
B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell-cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3'UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.
- Published
- 2011
- Full Text
- View/download PDF
32. T(3;7)(q27;q32) fuses BCL6 to a non-coding region at FRA7H near miR-29.
- Author
-
Schneider B, Nagel S, Kaufmann M, Winkelmann S, Bode J, Drexler HG, and MacLeod RA
- Subjects
- Base Sequence, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Lymphoma, B-Cell pathology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Molecular Sequence Data, Open Reading Frames, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Nucleic Acid, Tumor Cells, Cultured, Chromosome Fragile Sites genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 7 genetics, DNA-Binding Proteins physiology, Lymphoma, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics, MicroRNAs physiology, Translocation, Genetic genetics, Untranslated Regions genetics
- Published
- 2008
- Full Text
- View/download PDF
33. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma.
- Author
-
Iqbal J, Greiner TC, Patel K, Dave BJ, Smith L, Ji J, Wright G, Sanger WG, Pickering DL, Jain S, Horsman DE, Shen Y, Fu K, Weisenburger DD, Hans CP, Campo E, Gascoyne RD, Rosenwald A, Jaffe ES, Delabie J, Rimsza L, Ott G, Müller-Hermelink HK, Connors JM, Vose JM, McKeithan T, Staudt LM, and Chan WC
- Subjects
- DNA Mutational Analysis, Exons, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence, Introns, Lymphoma, Large B-Cell, Diffuse metabolism, Models, Genetic, Prognosis, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger metabolism, Time Factors, Translocation, Genetic, Treatment Outcome, DNA-Binding Proteins biosynthesis, Lymphoma, Large B-Cell, Diffuse genetics, Mutation
- Abstract
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
- Published
- 2007
- Full Text
- View/download PDF
34. Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin.
- Author
-
Traverse-Glehen A, Verney A, Baseggio L, Felman P, Callet-Bauchu E, Thieblemont C, Ffrench M, Magaud JP, Coiffier B, Berger F, and Salles G
- Subjects
- Humans, Lymphoma, B-Cell pathology, Lymphoma, Follicular pathology, Proto-Oncogene Proteins c-bcl-6, Splenic Neoplasms pathology, DNA-Binding Proteins genetics, Lymphoma, B-Cell genetics, Lymphoma, Follicular genetics, Mutation genetics, PAX5 Transcription Factor genetics, Proto-Oncogene Proteins c-pim-1 genetics, Splenic Neoplasms genetics, Transcription Factors genetics, fas Receptor genetics, rho GTP-Binding Proteins genetics
- Published
- 2007
- Full Text
- View/download PDF
35. Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas.
- Author
-
Bertrand P, Bastard C, Maingonnat C, Jardin F, Maisonneuve C, Courel MN, Ruminy P, Picquenot JM, and Tilly H
- Subjects
- Adult, Aged, Aged, 80 and over, Base Sequence, Burkitt Lymphoma genetics, Carrier Proteins genetics, Cell Transformation, Neoplastic genetics, Chromosomes, Human, Pair 2 genetics, Chromosomes, Human, Pair 2 ultrastructure, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 3 ultrastructure, Chromosomes, Human, Pair 7 genetics, Chromosomes, Human, Pair 7 ultrastructure, Chromosomes, Human, Pair 8 ultrastructure, Chromosomes, Human, Pair 9 genetics, Chromosomes, Human, Pair 9 ultrastructure, DNA-Binding Proteins genetics, Female, Humans, Ikaros Transcription Factor genetics, In Situ Hybridization, Fluorescence, Karyotyping, Male, Middle Aged, Molecular Sequence Data, Nuclear Proteins genetics, PAX5 Transcription Factor genetics, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Chromosome Breakage, Chromosomes, Human, Pair 8 genetics, Genes, myc, Lymphoma, B-Cell genetics, Translocation, Genetic genetics
- Abstract
Chromosomal translocations joining the immunoglobulin (IG) and MYC genes have been extensively reported in Burkitt's and non-Burkitt's lymphomas but data concerning MYC rearrangements with non-IG partners are scarce. In this study, 8q24 breakpoints from 17 B-cell lymphomas involving non-IG loci were mapped by fluorescence in situ hybridization (FISH). In seven cases the breakpoint was inside a small region encompassing MYC: in one t(7;8)(p12;q24) and two t(3;8)(q27;q24), it was telomeric to MYC whereas in four cases, one t(2;8)(p15;q24) and three t(8;9)(q24;p13) it was located in a 85 kb region encompassing MYC. In these seven cases, partner regions identified by FISH contained genes known to be involved in lymphomagenesis, namely BCL6, BCL11A, PAX5 and IKAROS. Breakpoints were cloned in two t(8;9)(q24;p13), 2.5 and 7 kb downstream from MYC and several hundred kb 5' to PAX5 on chromosome 9, joining MYC to ZCCHC7 and to ZBTB5 exon 2, two genes encoding zinc-finger proteins. In these seven cases, MYC expression measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) was significantly higher when compared to that of patients without 8q24 rearrangement (P=0.006). These results suggest that these rearrangements are the consequence of a non-random process targeting MYC together with non-IG genes involved in lymphocyte differentiation and lymphoma progression.
- Published
- 2007
- Full Text
- View/download PDF
36. Clinical and biological relevance of single-nucleotide polymorphisms and acquired somatic mutations of the BCL6 first intron in follicular lymphoma.
- Author
-
Jardin F, Ruminy P, Parmentier F, Picquenot JM, Courel MN, Bertrand P, Buchonnet G, Tilly H, and Bastard C
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, DNA genetics, DNA metabolism, DNA Mutational Analysis, DNA-Binding Proteins metabolism, Electrophoretic Mobility Shift Assay, Female, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Humans, Lymphoma, Follicular metabolism, Lymphoma, Large B-Cell, Diffuse genetics, Male, Middle Aged, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-bcl-6, Transcription Factors metabolism, Chromosomes, Human, Pair 3 genetics, DNA-Binding Proteins genetics, Introns genetics, Lymphoma, Follicular genetics, Mutation, Polymorphism, Single Nucleotide genetics, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
Genetic modifications of the BCL6 gene in lymphoma include translocations, deletions, and somatic mutations (SM) of the 5' noncoding region. Three single-nucleotide polymorphisms (SNPs) of the major mutation cluster region (MMC) have been reported, including two substitutions (397G/C, 502G/A) and one deletion (520DeltaT). Clinical and biological relevance of these SNPs are unknown. Based on a case-control study, BCL6 SNPs frequencies were assessed in 97 t(14;18) follicular lymphomas (FL) and in 54 lymphomas with 3q27 rearrangement. Allele frequencies were similar in the FL and controls groups. The 397 G/C genotype was correlated to a higher-grade transformation risk (P=0.02). SM were observed in 39.1% of FL and were characterized by a clustering distribution (hot spots spanning position 420-435, 106-127, and 590-600). No correlation between genotypes or acquired mutational status and BCL6 expression was demonstrated. However, gel mobility-shift assays, using SNPs containing probes show results representative for protein/DNA complexes. This study demonstrates that the first BCL6 intron is a highly variable region as a consequence of both SNP and SM, which may contribute to biology and outcome of FL.
- Published
- 2005
- Full Text
- View/download PDF
37. Low-grade follicular lymphoma with t(14;18) presents a homogeneous disease entity otherwise the rest comprises minor groups of heterogeneous disease entities with Bcl2 amplification, Bcl6 translocation or other gene aberrances.
- Author
-
Guo Y, Karube K, Kawano R, Yamaguchi T, Suzumiya J, Huang GS, and Ohshima K
- Subjects
- Biomarkers, Tumor, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Genetic Markers, Genotype, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Follicular classification, Phenotype, Proto-Oncogene Proteins c-bcl-6, DNA-Binding Proteins genetics, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, Proto-Oncogene Proteins c-bcl-2 genetics, Translocation, Genetic
- Abstract
Follicular lymphomas (FL) are morphologically classified into grades 1, 2, 3a and 3b by the World Health Organization. Bcl2, Bcl6 and CD10 are phenotypic markers of FL while the Bcl2 t(14;18) and Bcl6 t(3q27) gene translocations are common genetic changes. However, to date, there has been no integrated analysis based on phenotype, grade and genotype from large numbers of FL cases. We graded 261 cases of FL and determined their phenotypes and gene alterations. According to the antigen markers and gene alterations of 147 cases, we classified FL into typical and the others types. The typical group, which includes 69% cases of FL, is characterized by low histological grade (grade 1, 2), coexpression of BCL2 and CD10 and Bcl2 gene translocation. The rest comprises a small part of low-grade FL without Bcl2 gene translocation and high-grade (grade 3a, 3b) FL. These FLs include some heterogeneous disease entities. They are characterized by high histological grade (87%), no definite expression of BCL2 or CD10 and several kinds of gene aberrances including Bcl2 translocation, Bcl6 translocation, Bcl2 amplification or other unknown gene abnormality. Our findings indicate that typical FL presents a homogeneous disease entity whereas the rest comprises heterogeneous diseases entities.
- Published
- 2005
- Full Text
- View/download PDF
38. Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR.
- Author
-
Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, and Dyer MJ
- Subjects
- Base Sequence, Blotting, Southern, Carrier Proteins genetics, Chromosomes, Human, Pair 14, Cloning, Molecular, DNA-Binding Proteins genetics, Humans, Immunoglobulin mu-Chains genetics, Molecular Sequence Data, Nuclear Proteins genetics, PAX5 Transcription Factor, Polymerase Chain Reaction, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogene Proteins c-myc genetics, Receptor, Fibroblast Growth Factor, Type 3, Receptors, Fibroblast Growth Factor genetics, Repressor Proteins, Transcription Factors genetics, Tumor Cells, Cultured, Chromosome Breakage genetics, Gene Rearrangement, Genes, Switch genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin Switch Region genetics, Lymphoma genetics, Translocation, Genetic
- Abstract
Molecular cloning of immunoglobulin heavy chain (IGH) translocation breakpoints identifies genes of biological importance in the development of normal and malignant B cells. Long-distance inverse PCR (LDI-PCR) was first applied to amplification of IGH gene translocations targeted to the joining (IGHJ) regions. We report here successful amplification of the breakpoint of IGH translocations targeted to switch (IGHS) regions by LDI-PCR. To detect IGHS translocations, Southern blot assays using 5' and 3' switch probes were performed. Illegitimate Smu rearrangements were amplified from the 5' end (5'Smu LDI-PCR) from the alternative derivative chromosome, and those of Sgamma or Salpha were amplified from the 3' end (3'Sgamma or 3'alpha LDI-PCR) from the derivative chromosome 14. Using a combination of these methods, we have succeeded in amplifying IGHS translocation breakpoints involving FGFR3/MMSET on 4p16, BCL6 on 3q27, MYC on 8q24, IRTA1 on 1q21 and PAX5 on 9p13 as well as BCL11A on 2p13 and CCND3 on 6p21. The combination of LDI-PCR for IGHJ and IGHS allows rapid molecular cloning of almost all IGH gene translocation breakpoints.
- Published
- 2004
- Full Text
- View/download PDF
39. AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity.
- Author
-
Lossos IS, Levy R, and Alizadeh AA
- Subjects
- Cytidine Deaminase, Cytosine Deaminase genetics, DNA-Binding Proteins genetics, Germinal Center enzymology, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, B-Cell genetics, Lymphoma, Follicular enzymology, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse genetics, Proto-Oncogene Proteins c-bcl-6, Tumor Cells, Cultured, Cytosine Deaminase metabolism, Lymphoma, B-Cell enzymology, Lymphoma, Large B-Cell, Diffuse enzymology, Somatic Hypermutation, Immunoglobulin genetics
- Abstract
Activation-induced cytidine deaminase (AID), highly expressed in germinal center (GC)-lymphocytes, is involved in somatic hypermutation (SHM). We examined AID expression in diffuse large B-cell lymphomas (DLBCL) of germinal center B-cell (GCB)-like and activated B-cell (ABC)-like subtypes. These two types of DLBCL are characterized by high and low expression of GC-specific genes, respectively. AID expression was detected in both GCB- and ABC-like DLBCL, thus demonstrating a dissociation between AID expression and that of other GC genes. We also tested for the presence of intraclonal heterogeneity in immunoglobulin and BCL6 genes in those same tumors and in follicle center lymphomas (FCL) that transformed to DLBCL. The level of AID expression did not correlate with the presence of intraclonal sequence heterogeneity in either IgV(H) or BCL6. Our findings suggest that lymphomas maintain some but not all of the gene expression signatures of their normal B-cell counterparts. The fact that AID expression can be elevated without intraclonal sequence heterogeneity raises the possibility that other factors are required for SHM in these tumors. We found decreased levels of AID expression in DLBCL that evolved from FCL and which had acquired new mutations in their BCL6 genes. This dissociation suggests that AID expression and SHM may occur at the time prior to the clinical detection of transformed lymphoma.
- Published
- 2004
- Full Text
- View/download PDF
40. Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia.
- Author
-
Sarsotti E, Marugan I, Benet I, Terol MJ, Sanchez-Izquierdo D, Tormo M, Rubio-Moscardo F, Martinez-Climent JA, and García-Conde J
- Subjects
- Adult, Aged, Aged, 80 and over, Chromosome Deletion, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 17, Disease-Free Survival, Female, Follow-Up Studies, Humans, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Male, Middle Aged, Prognosis, Prospective Studies, Proto-Oncogene Proteins c-bcl-6, DNA-Binding Proteins genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was correlated with shorter treatment-free interval (TFI) compared to cases harboring only IgVH mutation (median, 55 months vs not reached; P=0.01), resembling the clinical course of unmutated IgVH cases (median TFI, 44 months). As expected, deletions of 17p13 (P53 locus) and 11q22 (ATM locus) were observed in cases with unmutated IgVH, except one patient who showed mutations of both IgVH and BCL-6. No other statistically significant differences were observed among the genetic subgroups. Our data indicate that BCL-6 mutations identify a subgroup of Binet stage A B-CLL patients with a high risk of progression despite the presence of mutated IgVH gene.
- Published
- 2004
- Full Text
- View/download PDF
41. The BCL6 gene in B-cell lymphomas with 3q27 translocations is expressed mainly from the rearranged allele irrespective of the partner gene.
- Author
-
Lossos IS, Akasaka T, Martinez-Climent JA, Siebert R, and Levy R
- Subjects
- Alleles, DNA-Binding Proteins biosynthesis, Gene Rearrangement, Humans, Mutation, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger analysis, Repressor Proteins biosynthesis, Transcription Factors biosynthesis, Tumor Cells, Cultured, Chromosomes, Human, Pair 3, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, Lymphoma, B-Cell genetics, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Transcription Factors genetics, Translocation, Genetic
- 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.
- Published
- 2003
- Full Text
- View/download PDF
42. Diagnostic role and prognostic significance of a simplified immunophenotypic classification of mature B cell chronic lymphoid leukemias.
- Author
-
Cro L, Guffanti A, Colombi M, Cesana B, Grimoldi MG, Patriarca C, Goldaniga M, Neri A, Intini D, Cortelezzi A, Maiolo AT, and Baldini L
- Subjects
- Adult, Aged, Aged, 80 and over, Antigens, CD immunology, Blotting, Western, Chromosome Aberrations, DNA-Binding Proteins genetics, Female, Follow-Up Studies, Genes, bcl-1 physiology, Humans, Immunoglobulins immunology, Immunoglobulins metabolism, Immunophenotyping, Karyotyping, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocytes blood, Lymphocytes metabolism, Male, Middle Aged, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-6, Sensitivity and Specificity, Survival Rate, Transcription Factors genetics, CD5 Antigens immunology, Gene Expression Regulation, Neoplastic, Lectins immunology, Leukemia, Lymphocytic, Chronic, B-Cell classification, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Membrane Proteins immunology, Receptors, IgE immunology
- Abstract
We verified the diagnostic and prognostic role of a simplified immunophenotypic classification (IC) in a series of 258 patients (M/F: 1.4; median age: 64 years; median follow-up: 64 months; 75 deaths) with mature B cell lymphoid leukemias (MBC-LL) for whom no histopathological diagnosis was available because of minimal or no lymph node involvement. The IC was based on the reactivity of three pivotal immunophenotypic markers: CD5, CD23 and SIg intensity. On the basis of different expression patterns, we identified four diagnostic clusters (C) characterized by distinct clinico-biological features and different prognoses: C1 (149 patients) identified most classical B cell chronic lymphocytic leukemias (CLL-type cluster; SIg(dim)/CD5+/CD23+); C2, 38 patients whose clinico-hematological characteristics were intermediate between C1 and C3 (CLL-variant cluster; SIg(bright)/CD5+/CD23+/-or SIg(dim)/CD5-/-/CD23 indifferent); C3 (16 patients) most situations consistent with mantle cell lymphoma in leukemic phase (MCL-type cluster; SIg(bright)/CD5+/CD23-); and C4, 55 cases, most of whom were consistent with leukemic phase lymphoplasmacytic/splenic marginal zone lymphomas (LP/S-type cluster; SIg(bright)/CD5-/+/CD23 indifferent). At univariate survival analysis, prognosis worsened from C1 to C4, C2 and C3 (P = 0.0001), and this was maintained at multivariate analysis (P = 0.006), together with CD11c expression (P = 0.0043), age at diagnosis (cut-off 70 years; P = 0.0008) and platelet count (cut-off 140 x 10(9)/l; P = 0.0034). Besides recognising the two well-known situations of classic B-CLL and MCL, our IC identified situations with distinct prognostic and/or clinical behaviors.
- Published
- 2003
- Full Text
- View/download PDF
43. Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements.
- Author
-
Jardin F, Buchonnet G, Parmentier F, Contentin N, Leprêtre S, Lenain P, Picquenot JM, Laberge S, Bertrand P, Stamatoullas A, D'Anjou J, Tilly H, and Bastard C
- Subjects
- Biopsy, Blotting, Southern, Chromosome Aberrations, DNA Primers chemistry, DNA-Binding Proteins metabolism, Gene Expression Regulation, Leukemic genetics, Hodgkin Disease genetics, Hodgkin Disease metabolism, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Lymph Nodes metabolism, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger metabolism, RNA, Neoplasm metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors metabolism, Translocation, Genetic, Tumor Cells, Cultured pathology, Up-Regulation, Chromosomes, Human, Pair 3 genetics, DNA-Binding Proteins genetics, Gene Rearrangement, Lymphoma, Follicular genetics, Lymphoma, Follicular metabolism, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27(+) DLBCL (n = 20) cases and 67% of 3q27(+) cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 +/- 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 +/- 1.82; P < 0.001), MCL (1.23 +/- 0.73), MZL (1.49 +/- 1.3), HD (1.60 +/- 1.00), TCL (1.75 +/- 1.64), but also RH (3.91 +/- 3.12) or NM (1.95 +/- 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P < 0.001). Conversely, we failed to show any difference between 3q27(+) DLBCL and 3q27(-)DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27(+) FCL (n = 10) was significantly lower than in 3q27(-) FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.
- Published
- 2002
- Full Text
- View/download PDF
44. Follicular lymphoma without t(14;18) and with BCL-6 rearrangement: a lymphoma subtype with distinct pathological, molecular and clinical characteristics.
- Author
-
Jardin F, Gaulard P, Buchonnet G, Contentin N, Leprêtre S, Lenain P, Stamatoullas A, Picquenot JM, Duval C, Parmentier F, Tilly H, and Bastard C
- Subjects
- Adult, Aged, Biomarkers, Tumor metabolism, Chromosomes, Human, Pair 3 genetics, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins metabolism, Female, Humans, Immunoenzyme Techniques, Immunophenotyping, Karyotyping, Lymphoma, Follicular metabolism, Male, Middle Aged, Mutation, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-bcl-6, Survival Rate, Transcription Factors metabolism, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, DNA-Binding Proteins genetics, Gene Rearrangement, Lymphoma, Follicular genetics, Proto-Oncogene Proteins genetics, Transcription Factors genetics, Translocation, Genetic
- Abstract
Translocations involving the BCL-6 gene are frequently observed in diffuse large B cell lymphoma, but have rarely been reported in follicular lymphoma (FL). We studied a distinct cohort of FLs with a 3q27/BCL-6 gene rearrangement, but lacking the t(14;18) translocation. In 13/15 cases, translocations involved the 3q27 and the 14q32 regions. All cases displayed a marked follicular growth pattern and, in some instances, a monocytoid component. Tumor cells were CD5(-) CD20(+) CD23(-) CD43(-) BCL-6(+), and in the main CD10 negative (n = 10, 71%) and BCL-2 negative (n = 11, 78%). When compared to 20 typical t(14;18)(+) FLs, the presence of large follicles (P = 0.01) and a CD10(-)/BCL-2(-) phenotype were more frequently observed (P = 0.001) in our cohort. Clonal mutations arising in the BCL-6 first intron were observed in 5/7 cases with evidence of intraclonal heterogeneity, consistent with a germinal center origin. No significant difference was found in comparison to t(14;18)(+) FL regarding age, sex, performance status, bone marrow involvement or overall survival. However, in the 3q27(+) FL group, a stage III/IV disease and a bulky mass were less frequently observed. This study indicates that 3q27(+) FL without t(14;18) translocation have peculiar clinico-pathologic features and may correspond to a rare and distinct subtype of lymphoma originating from the germinal center.
- Published
- 2002
- Full Text
- View/download PDF
45. BCL-6 mRNA expression in higher grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5' regulatory region of the BCL-6 gene.
- Author
-
Lossos IS, Warnke R, and Levy R
- Subjects
- DNA Primers chemistry, Humans, Immunoenzyme Techniques, Polymerase Chain Reaction, Proto-Oncogene Proteins c-bcl-6, 5' Untranslated Regions genetics, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins genetics, Lymphoma, B-Cell genetics, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse genetics, Mutation, Proto-Oncogene Proteins genetics, RNA, Messenger metabolism, RNA, Neoplasm metabolism, Transcription Factors genetics
- Abstract
Follicle center lymphoma (FCL) is an indolent low-grade B cell non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive diffuse large B cell lymphoma (DLBCL). Histological transformation of FCL is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is commonly implicated in the pathogenesis of DLBCL and its expression may be altered by clonal rearrangements and somatic point mutations in its 5' non-translated regulatory region. Recently, somatic mutations of the BCL-6 gene were associated with the transformation process. Here, we examined BCL-6 mRNA expression and BCL-6 mutations in paired biopsies from the same patients obtained at the time of FCL diagnosis and after transformation. BCL-6 mRNA expression markedly increased upon transformation (1.9- to 4.8-fold) in three cases, remained unchanged in one case and decreased compared to the diagnosis FCL specimens in four cases. The three specimens that demonstrated an increase in the BCL-6 mRNA expression upon transformation harbored BCL-6 gene mutations in the 5' region of the first intron that overlapped with the previously reported negative regulatory region of the gene. Accumulation of new mutations in this region was not observed in DLBCL biopsies in which the BCL-6 mRNA expression did not increase. The present study demonstrates that although BCL-6 gene mutations do accumulate during the transformation process and, depending on their location within the first intron, may deregulate BCL-6 mRNA expression, increase in BCL-6 mRNA expression is not uniformly required for transformation from FCL to DLBCL.
- Published
- 2002
- Full Text
- View/download PDF
46. Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma.
- Author
-
Vitolo U, Botto B, Capello D, Vivenza D, Zagonel V, Gloghini A, Novero D, Parvis G, Calvi R, Ariatti C, Milan I, Bertini M, Boccomini C, Freilone R, Pregno P, Orsucci L, Palestro G, Saglio G, Carbone A, Gallo E, and Gaidano G
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bleomycin administration & dosage, Carmustine administration & dosage, Chromosomes, Human, Pair 3 genetics, Cyclophosphamide administration & dosage, Cytarabine administration & dosage, DNA Mutational Analysis, DNA, Neoplasm genetics, Disease-Free Survival, Doxorubicin administration & dosage, Etoposide administration & dosage, Female, Genes, bcl-2, Humans, Life Tables, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Male, Melphalan administration & dosage, Methotrexate administration & dosage, Middle Aged, Neoplasm Staging, Prednisolone administration & dosage, Prednisone administration & dosage, Prognosis, Proto-Oncogene Mas, Proto-Oncogene Proteins c-bcl-6, Treatment Outcome, Vincristine administration & dosage, DNA-Binding Proteins genetics, Lymphoma, Large B-Cell, Diffuse genetics, Neoplasm Proteins genetics, Point Mutation, Proto-Oncogene Proteins genetics, Proto-Oncogenes, Transcription Factors genetics
- Abstract
Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.
- Published
- 2002
- Full Text
- View/download PDF
47. Molecular heterogeneity of splenic marginal zone lymphomas: analysis of mutations in the 5' non-coding region of the bcl-6 gene.
- Author
-
Mateo MS, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martínez P, and Piris MA
- Subjects
- ADP-ribosyl Cyclase, ADP-ribosyl Cyclase 1, Antigens, Differentiation analysis, Humans, Membrane Glycoproteins, NAD+ Nucleosidase analysis, Proto-Oncogene Proteins c-bcl-6, 5' Untranslated Regions genetics, Antigens, CD, DNA-Binding Proteins genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, B-Cell genetics, Mutation, Proto-Oncogene Proteins genetics, Splenic Neoplasms genetics, Transcription Factors genetics
- Abstract
Splenic marginal zone lymphoma (SMZL) has been recognized as a distinctive type of small B cell lymphoma, and defined on the basis of its morphological, phenotypic, clinical and molecular characteristics. In spite of this, the borders of the entity, the homogeneity of the cases and the presumably cell origin of SMZL remain controversial issues. The frequency of mutation in the 5' non-coding region of the bcl-6 gene has been used as a marker of germinal center derivation, which may be used to establish the molecular heterogeneity of different non-Hodgkin lymphoma (NHL) types. This roughly parallels the characteristics and frequency of the somatic hypermutations found in the immunoglobulin heavy chain variable region (IgVH) genes. This study analyzed mutations of bcl-6 in the 5' non-coding region in 22 SMZL cases and, for the purpose of comparison with different B cell subsets, in microdissected germinal centers, mantle zones and marginal zone subpopulations from reactive splenic lymphoid follicles. A majority of the SMZL cases studied, 19/22 (87%), bear unmutated bcl-6 gene, while mutation was only observed in 3/22 (13%) cases. Analysis of normal B cell subpopulations showed bcl-6 hypermutation in 3/10 (30%) germinal center clones, 5/14 (35%) marginal zone clones; and unmutated sequences in all clones derived from mantle cells. The frequency of these mutations in normal spleen confirms previous findings on the hypermutation IgVH process in normal B cell populations. The data presented here support the existence of molecular heterogeneity in this entity, and give additional results in favor of the hypothesis that, in spite of initial morphological observations, a significant proportion of SMZL cases could derive from an unmutated naive precursor, different from the marginal zone, and possibly located in the mantle zone of splenic lymphoid follicles. Thus the marginal zone differentiation of these tumors could be related more with the splenic microenvironment than it is to the histogenetic characteristics of the tumor.
- Published
- 2001
- Full Text
- View/download PDF
48. De novo acute B cell leukemia/lymphoma with t(14;18).
- Author
-
Stamatoullas A, Buchonnet G, Lepretre S, Lenain P, Lenormand B, Duval C, Callat MP, Gaulard P, Bastard C, and Tilly H
- Subjects
- Adult, Antineoplastic Agents therapeutic use, Blast Crisis drug therapy, Blast Crisis genetics, Blast Crisis pathology, Bone Marrow pathology, Bone Marrow Transplantation, Burkitt Lymphoma drug therapy, Burkitt Lymphoma pathology, Burkitt Lymphoma therapy, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, DNA, Neoplasm genetics, DNA-Binding Proteins genetics, Disease Progression, Female, Genes, bcl-2, Genes, myc, Genes, p53, Humans, Immunophenotyping, Leukemic Infiltration, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell pathology, Lymphoma, B-Cell therapy, Lymphoma, Follicular drug therapy, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, Lymphoma, Follicular therapy, Male, Meninges pathology, Middle Aged, Neoplastic Cells, Circulating, Prognosis, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-6, Recurrence, Salvage Therapy, Transcription Factors genetics, Treatment Failure, Burkitt Lymphoma genetics, Chromosomes, Human, Pair 14 ultrastructure, Chromosomes, Human, Pair 18 ultrastructure, Lymphoma, B-Cell genetics, Translocation, Genetic
- Abstract
The t(14;18)(q32;q21) translocation is the most common translocation in B cell malignancies being found in 80% of follicular lymphomas and about 20% of diffuse large B cell lymphomas. Only rare cases of de novo acute B cell lymphoblastic leukemia with t(14;18) have been described. We describe five cases of this entity which appears to have very homogeneous clinical, phenotypic and genotypic features. None of these patients had prior history of follicular lymphoma. The disease was characterized by acute clinical features with nodal and/or extranodal disease, massive bone marrow infiltration and rapid increase of circulating blast cells of mature B cell phenotype. All patients disclosed complex chromosomal and molecular abnormalities involving at least the BCL-2 and c-MYC genes. Furthermore, three patients had evidence of BCL-6 involvement and one patient had a p53 mutation. Despite intensive chemotherapy, including for two patients allogeneic bone marrow transplantation in first complete remission, all patients died within a few months. Neuro-meningeal relapse occurred in three of the five patients in spite of neuro-meningeal prophylaxis. De novo leukemia/lymphoma with t(14;18) is a rare entity with a very poor prognosis. Whether early bone marrow transplant could modify the natural history of the disease remains to be determined. An intensive neuro-meningeal prophylaxis appears to be mandatory in these patients.
- Published
- 2000
- Full Text
- View/download PDF
49. Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes.
- Author
-
Capello D, Fais F, Vivenza D, Migliaretti G, Chiorazzi N, Gaidano G, and Ferrarini M
- Subjects
- Base Sequence, Gene Rearrangement, B-Lymphocyte, Genes, Immunoglobulin, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Light Chains genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Point Mutation, Proto-Oncogene Mas, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogenes, Tumor Cells, Cultured, Zinc Fingers, DNA-Binding Proteins genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell classification, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
Although B cell chronic lymphocytic leukemia (B-CLL) has been traditionally viewed as a tumor of virgin B cells, this notion has been recently questioned by data suggesting that a fraction of B-CLL derives from antigen experienced B cells. In order to further clarify the histogenetic derivation of this lymphoproliferation, we have analyzed the DNA sequences of the 5' non-coding region of BCL-6 proto-oncogene in 28 cases of B-CLL. Mutations of BCL-6 proto-oncogene, a zinc finger transcription factor implicated in lymphoma development, represent a histogenetic marker of B cell transit through the germinal center (GC) and occur frequently in B cell malignancies derived from GC or post-GC B cells. For comparison, the same tumor panel was analyzed for somatic mutations of the rearranged immunoglobulin variable (IgV) genes, which are known to be acquired at the time of B cell transit through the GC. Sequence analyses of BCL-6 and IgV genes allowed the definition of three groups of B-CLL. Group I B-CLL displayed mutations of both BCL-6 and IgV genes (10/28; 36%). Group II B-CLL displayed mutated IgV genes, but a germline BCL-6 gene (5/28; 18%). Finally, group III B-CLL included the remaining cases (13/28; 46%) that were characterized by the absence of somatic mutations of both BCL-6 and IgV genes. Overall, the distribution of BCL-6 and IgV mutations in B-CLL reinforce the notion that this leukemia is histogenetically heterogeneous and that a substantial subgroup of these lymphoproliferations derives from post-germinal center B cells.
- Published
- 2000
- Full Text
- View/download PDF
50. MUM1: a step ahead toward the understanding of lymphoma histogenesis.
- Author
-
Gaidano G and Carbone A
- Subjects
- Biomarkers, Tumor genetics, Cell Differentiation, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins genetics, Genes, Immunoglobulin, Germinal Center pathology, Humans, Interferon Regulatory Factors, Lymphoma, B-Cell classification, Lymphoma, B-Cell genetics, Models, Biological, Mutation, Phenotype, Plasma Cells pathology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-6, Transcription Factors genetics, Biomarkers, Tumor analysis, DNA-Binding Proteins analysis, Lymphoma, B-Cell pathology, Transcription Factors analysis
- Abstract
In recent times, the field of B cell lymphoma histogenesis has progressed rapidly due to the increasing availability of histogenetic markers. Genotypic markers of B cell histogenesis are represented by mutations of IgV and BCL-6 genes, which are somatically acquired at the time of B cell transit through the germinal center (GC). Phenotypic markers are represented by BCL-6 and CD138/syndecan-1 protein expression and allow the distinction between GC and post-GC B cells. On this basis, lymphomas may be histogenetically distinguished into: (1) lymphomas devoid of somatic IgV and BCL-6 hypermutation, which derive from pre-germinal center B cells; (2) lymphomas associated with somatic IgV and/or BCL-6 hypermutation and BCL-6 expression, which closely reflect germinal center B cells; and (3) lymphomas associated with somatic IgV and/or BCL-6 hypermutation, as well as CD138/syndecan-1 positivity, representing lymphomas of post-germinal center B cells. In the March issue of Leukemia, Tsuboi et al report on the expression pattern of MUM1 in normal lymphoid tissues and in lymphoma. Because expression of MUM1 protein appears to be strictly regulated during lymphoid differentiation, and because expression of the molecule is retained upon neoplastic transformation, MUM1 may be added to the panel of phenotypic markers of B cell lymphoma histogenesis. In particular, MUM1 may provide a marker for the identification of transition from BCL-6 positivity (GC B cells) to CD138 expression (immunoblasts and plasma cells). These studies are of potential clinical value, since in some B cell malignancies, histogenesis may influence prognosis.
- Published
- 2000
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.